Cement products and methods of making and using the same

ABSTRACT

Disclosed are cement products, methods of forming cement using the cement product, and methods of using the cement product in orthopedic and dental applications. Generally, the disclosed cement product includes a first component and a second component. The first component comprises a polymerizable resin comprising ethylenic unsaturated double bond, a suitable glycidyl group and/or a suitable isocyanate group. The second component includes a compound comprising more than one type of amine selected from the group consisting of primary amine, secondary amines, tertiary amines and quaternary amines. Alternatively, the second component includes a compound comprising a suitable mercapto (SH—) group, a hindered amine or a dimethylthiotoluenediamine (DMTDA). Optionally, the cement product includes a filler and/or a bioactive component to promote bone formation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/461,138 filed on Aug. 15, 2014, which issued as U.S. Pat. No.9,358,319 on Jun. 7, 2016, which is a continuation of U.S. patentapplication Ser. No. 12/200,918 filed on Aug. 28, 2008, which issued asU.S. Pat. No. 8,815,973 on Aug. 26, 2014, and claims the benefit of U.S.Provisional Patent Application No. 60/968,462 filed on Aug. 28, 2007,the disclosures of which are incorporated by reference in theirentireties.

BACKGROUND OF THE INVENTION

The demand for restorative cement products useful in orthopedic anddental treatments has been increasing, in part, as a consequence oflengthening lifespans and a steadily larger pool of candidates fororthopedic and dental treatments. A second factor driving demand is theincreasing tendency among individuals to maintain or adopt a more activelifestyle as they age. This trend makes procedures that use restorativecement products more beneficial and more desirable. A third factordriving the demand for restorative cement products is the development ofnew techniques that use such cement products.

One disorder that can benefit from improvements to restorative cementproducts is osteoporosis. Osteoporosis is a chronic bone disease inwhich the amount of bone is decreased and the structural integrity ofbone is impaired. Cancellous bone becomes more porous and cortical bonebecomes thinner, making it weaker and more likely to fracture under anormal physiological stress. Eventually, even low impact trauma canresult in a fracture and start the victim on a path that will compromisequality of life and, in nearly one third of cases, lead to death.

In the United States, 10 million people have osteoporosis andapproximately 32 million more people have low bone mass (calledosteopenia), placing them at risk for osteoporosis and osteoporoticfractures. 80% of these people are women. By the age of 65, 50% of womenwill suffer from osteoporosis, which increases to nearly 100% by age 80.A white female has a 33% chance for a vertebral fracture andapproximately a 20-25% chance for a hip fracture in her lifetime. Theresults are devastating; approximately 15% of osteoporotic patients willhave fractures yearly. These 1.5 million fractures occur in 300,000hips, 700,000 hips, 250,000 wrists, and 300,000 other locations, such asthe rib and ankle.

Among the most widely used cement products in orthopedic and dentalsystems are those based on the polymerizable acrylate resinpolymethylmethacrylate (PMMA). PMMA has been used extensively inorthopedic and dental applications. More recent applications include theuse of PMMA to treat vertebral compression fractures as a result oftrauma or osteoporosis.

PMMA cements are typically prepared from two components: a liquid and apowder. The liquid includes methylmethacrylate (MMA) monomers, anaccelerator, and/or an inhibitor. The powder includes PMMA microspheres,a polymerization initiator, and/or a radio-opacifier. This system hasbeen in procedures that polymerize the cement in situ, i.e., at the siteof injury being treated. For example, PMMA cements have been used inorthopedic implant surgery to bond the implant to bone and to treatvertebral compression fractures using vertebroplasty and Kyphoplasty™.

However, some concern has been expressed that the exothermicpolymerization of PMMA in situ can lead to thermal necrosis. Forexample, it has been reported that previously studied bone cementproducts produce a maximum rise in temperature ranging from 80° C. to124° C. Serbetci et al., “Mechanical and Thermal Properties ofHydroxyapatite-Impregnated Bone Cement,” Turk. J. Med. Sci., 30: 543-549(2000). These temperatures exceed the limits for avoiding thermal tissuedamage and, thus, have led to concern regarding the heat generated bybone cement polymerization in situ.

As PMMA has found clinical utility in treating osteoporosis,limitations, in addition to its exotherm, have been observed. PMMAcements have also been used to treat bone damage in patients withosteoporosis. According to the National Osteoporosis Foundation, about700,000 vertebral fractures occur annually; and approximately 270,000 ofthese fractures are painful and clinically diagnosed. While mostpatients are treated non-operatively, those that do not respond toconservative treatment can be left with persistent pain and limitedmobility. These patients are potential candidates for vertebroplasty orKyphoplasty™ procedures: two minimally invasive procedures that use PMMAto treat vertebral compression fractures. However during vertebroplastyor Kyphoplasty™, leakage of liquid from low viscosity PMMA bone cementscan result in “soft tissue damage as well as nerve root pain andcompression. Other reported complications generally associated with theuse of bone cements in the spine include pulmonary embolism, respiratoryand cardiac failure, abdominal intrusions/ileus, and death. Each ofthese types of complications has been reported in conjunction with theuse of these products in both vertebroplasty and kyphoplastyprocedures.” 2004 FDA Public Health Web Notification “ComplicationsRelated to the Use of Bone Cement in Treating Compression Fractures ofthe Spine” (issued by Laura Alonge, Office of Surveillance andBiometrics).

Additionally, unreacted components of PMMA cements have been identifiedas a potential source of toxicity in the body. Thus, besides toxicitydue to thermal necrosis, studies have suggested that certain PMMA cementproducts can produce toxicity due to leaching of unconsumed MMA monomersand/or the polymerization activator. Liso et al., “Analysis of theLeaching and Toxicity of New Amine Activators for Curing of Acrylic BoneCements and Composites”, Biomaterials 18: 15-20 (1997).

The need for new restorative cement products that address theaforementioned concerns is widely recognized in the field.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a number of cement products. One cementproduct includes a first component and a second component. The firstcomponent comprises a polymerizable resin that includes an ethylenicunsaturated double bond. Alternatively, in addition to or instead of theethylenic unsaturated double bond, the first component comprises apolymerizable resin that includes a suitable glycidyl ether; a suitableglycidyl ester; a suitable ester containing glycidyl ether; a suitablecarbonate containing glycidyl ether; and/or a suitable ester orcarbonate containing isocyanate. Thus, the first component can alsocomprise a mixture of ethylenic unsaturated double bonds, glycidylgroups, or isocyanate groups. The second component includes a compoundthat includes more than one type of amine selected from the groupconsisting of a primary amine, a secondary amine, a tertiary amine, or aquaternary amine. Alternatively, the second component includes acompound comprising a suitable mercapto (—SH) group or acetoacetonategroup. The compounds in the second component can be furtherfunctionalized with ester or carbonate groups.

The cement product can also, optionally, further include an additionalfiller such as an inert filler or a bioactive component that promotesbone growth, provides a tissue scaffold, or provides for the creation ofporosity.

In some embodiments, the cement product further comprises a thirdcomponent including an oxygen-containing ring structure that is capableof reacting in a polymerization reaction with the first component, thesecond component, or both. In other embodiments, the first componentfurther comprises an oxygen-containing ring structure that is capable ofreacting in a polymerization reaction with another group on firstcomponent, the second component, or both.

The invention also provides a method of forming cement, the methodcomprising mixing the first component of the cement product with thesecond component of the cement product to thereby form cement. Theinvention further provides a method of treating a patient in need oftreatment for a bone defect, wherein the method includes forming cementaccording to the method of invention and delivering the cement to thedefective bone as part of a procedure for repairing the bone defect.

The invention is based, in part, on the discovery that the polymerizableresin of the first component can be combined with the amine-containingcompound of the second component in a polymerizing cement-hardeningreaction that produces only a mild increase in temperature or noincrease in temperature at all. Consequently, even when the product isdelivered to the site of restoration and cement-hardening polymerizationreactions proceeds in situ, the cement product can be used with less (orwithout any) concern for thermal necrosis.

The invention is also based, in part, on the discovery that the cementproduct can be formulated so that, when the components of the cementproduct are mixed, the resulting cement is injectable. In other words,the first, second, and optional third components can be formulated toproduce a cement mix that has the appropriate flowability properties foran injectable cement. Moreover, the improved flowability of the mixturecan secure more homogeneous dispersion and mixing of the components upondelivery of the cement. The disclosed first, second, and optional thirdcomponents can also be formulated so that when combined, the componentsreact to form a crosslinked thermoset network that is ultimately notsoluble and not fusible and consumes nearly all monomers and oligomersthus reducing the amount of unreacted starting material or by-productsthat can leach from the formed cement. Additionally, theamine-containing compound of the second component in the cement productcan, in certain embodiments, reduce or eliminate the need for aleachable free radical polymerization initiator and/or a chemicalaccelerator such as those used in the thermoplastic PMMA bone cementproducts. Thus, the aforementioned advantages can reduce the risks ofchemical tissue damage associated with the cement product disclosedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing temperature rise relative to time forcompositions of the invention that include indicated molecular weightsof PEI.

FIG. 2 is a graph showing temperature rise relative to time forcompositions of the invention that include indicated molecular weightsof PEI.

FIG. 3 is a graph showing temperature rise relative to time forcompositions of the invention that include indicated molecular weightsof PEI.

FIG. 4 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI to pentaerythritol triacrylate.

FIG. 5 is a graph showing temperature rise relative to time forcompositions of the invention that include indicated mole ratios of PEIto propoxylated (3) TMPTA.

FIG. 6 is a graph showing temperature rise relative to time forcompositions of the invention that include indicated mole ratios of PEIto propoxylated (5) glycerol ethoxylated bisphenol-A-triacrylate.

FIG. 7 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI (doped with CQ 222 pm) to pentaerythritol triacrylate.

FIG. 8 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI (doped with CQ 222 pm) to propoxylated (3) TMPTA.

FIG. 9 is a graph showing temperature rise relative to time forcompositions of the invention that include the 1:1 mole ratio of PEI(doped with CQ 222 pm) to propoxylated (5) glycerol ethoxylatedbisphenol-A-triacrylate.

FIG. 10 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI (doped with CQ 0.5%) to pentaerythritol triacrylate.

FIG. 11 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI (doped with CQ 0.5%) to propoxylated (3) TMPTA.

FIG. 12 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI (doped with CQ 0.5%) to propoxylated (5) glycerol ethoxylatedbisphenol-A-triacrylate.

FIG. 13 is a graph showing temperature rise relative to time forcompositions of the invention that include a 1:1 mole ratio of PEI(doped with CQ 0.5%) to propoxylated (6) TMPTA.

FIG. 14 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI to ethoxylated (2) bisphenol-A-diacrylate.

FIG. 15 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI to ethoxylated (4) bisphenol-A-diacrylate.

FIG. 16 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI (doped with CQ 222 pm) to ethoxylated (2) bisphenol-A-diacrylate.

FIG. 17 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI (doped with CQ 222 pm) to ethoxylated (4) bisphenol-A-diacrylate.

FIG. 18 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI (doped with CQ 0.5%) to ethoxylated (2) bisphenol-A-diacrylate.

FIG. 19 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI (doped with CQ 0.5%) to ethoxylated (4) bisphenol-A-diacrylate.

FIG. 20 is a graph showing temperature rise relative to time forcompositions of the invention that include the indicated mole ratios ofPEI to a first component that includes an equimolar mixture ofE(2)BisGMA, BisGMA, and GMA.

FIG. 21 is a graph showing strength relative to cure time for two cementformulations.

FIG. 22 is a graph showing strength relative to cure time for two cementformulations in the presence or absence of simulated body fluid (SBF).

FIG. 23 is a graph showing strength relative to cure time for two cementformulations in the presence or absence of simulated body fluid (SBF).

FIG. 24 is a graph showing strength relative to cure time for two cementformulations in the presence or absence of simulated body fluid (SBF).

FIG. 25 is graph showing temperature rise relative to time forcompositions of the invention that include the indicatedepoxy-containing first component and 15% ZnS.

FIG. 26 is graph showing temperature rise relative to time forcompositions of the invention that include the indicatedepoxy-containing first component and the indicated amounts of ZnS andZnO.

DETAILED DESCRIPTION OF THE INVENTION

The cement product of the present invention includes at least a firstand a second component. The first component includes a polymerizableresin. In one embodiment, the second component includes a compoundcomprising more than one type of amine selected from the groupconsisting of a primary amine, a secondary amine, a tertiary amine, or aquaternary amine. In another embodiment, the second component includes acompound comprising a suitable mercapto (—SH) group or an acetoacetonategroup. The aforementioned embodiments of the second component are notmutually exclusive, such that a second component can include varyingamounts of compounds of each of the aforementioned embodiments. Thecement products of the present invention can further comprise a compoundcomprising an oxygen-containing ring, e.g., in the first or thirdcomponent. The cement products of the present invention can also furthercomprise a filler such as an inert filler or a bioactive component thatpromotes bone growth. Each component of the cement product can also,optionally, include additional materials.

The first component of the cement product includes one or morebiocompatible polymerizable resins. Polymerizable groups are those thatcan be polymerized, e.g., by Michael addition reactions, by cations suchas carbocations, by ion radicals, by free radicals or combinationsthereof. Polymerizable groups can also be polymerized by reactions suchas (a) a glycidyl (oxirane)-amine ring opening addition reaction, (b) aglycidyl and polyorganosulfide reaction, (c) a glycidyl-carboxylic acidreaction, (d) a glycidyl-glycidyl reaction. Preferred polymerizableresins include one or more ethylenically unsaturated polymerizablegroup, a glycidyl group, or an isocyanate group.

In some embodiments, preferred polymerizable resins includeethylenically unsaturated double bonds and functional groups known to bebiodegradable. Exemplary functional groups include one or more acrylate,methacrylate, ester, ether, amide, carbonate, urethane, oxirane, orhydroxyl groups on the side chain or main chain of such resins. Morepreferred side chains include imide, isocyanate, phenolic, mercapto,epoxide, diepoxide, aldehyde, anhydride, and dianhydride functionalgroups.

Sterically hindered functional groups can be used to lengthen workingtime, set time or cure time. For example, the working times ofmethacrylates are much longer than acrylates. Furthermore, working timescan be lengthened by using lower molecular weight components.

Polymerizable resins suitable for use in the first component includeacrylic resins. Suitable acrylic resins include methyl acrylate, methylmethacrylate, ethyl acrylate, ethyl methacrylate, propyl acrylate,propyl methacrylate, isopropyl acrylate, isopropyl methacrylate,2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate (“HEMA”),hydroxypropyl acrylate, hydroxypropyl methacrylate, tetrahydrofurfurylacrylate, tetrahydrofurfuryl methacrylate, glycerol mono- anddi-acrylate, glycerol mono- and dimethacrylate, ethyleneglycoldiacrylate, ethyleneglycol dimethacrylate, polyethyleneglycol diacrylatewhere the number of repeating ethylene oxide units varies from 2 to 30,polyethyleneglycol dimethacrylate where the number of repeating ethyleneoxide units varies from 2 to 30, especially triethylene glycoldimethacrylate (“TEGDMA”), neopentyl glycol diacrylate, neopentylglycoldimethacrylate, trimethylolpropane triacrylate, trimethylolpropanetrimethacrylate, mono-, di-, tri-, and tetra-acrylates and methacrylatesof pentaerythritol and dipentaerythritol, 1,3-butanediol diacrylate,1,3-butanediol dimethacrylate, 1,4-butanediol diacrylate, 1,4-butanedioldimethacrylate, 1,6-hexane diol diacrylate, 1,6-hexanedioldimethacrylate, di-2-methacryloyloxethyl hexamethylene dicarbamate,di-2-methacryloyloxyethyl trimethylhexamethylene dicarbamate,di-2-methacryloyl oxyethyl dimethylbenzene dicarbamate,methylene-bis-2-methacryloxyethyl-4-cyclohexyl carbamate,di-2-methacryloxyethyl-dimethylcyclohexane dicarbamate,methylene-bis-2-methacryloxyethyl-4-cyclohexyl carbamate,di-1-methyl-2-methacryloxyethyl-trimethyl-hexamethylene dicarbamate,di-1-methyl-2-methacryloxyethyl-dimethylbenzene dicarbamate,di-1-methyl-2-methacryloxyethyl-dimethylcyclohexane dicarbamate,methylene-bis-1-methyl-2-methacryloxyethyl-4-cyclohexyl carbamate,di-1-chloromethyl-2-methacryloxyethyl-hexamethylene dicarbamate,di-1-chloromethyl-2-methacryloxyethyl-trimethylhexamethylenedicarbamate, di-1-chloromethyl-2-methacryloxyethyl-dimethylbenzenedicarbamate, di-1-chloromethyl-2-methacryloxyethyl-dimethylcyclohexanedicarbamate, methylene-bis-2-methacryloxyethyl-4-cyclohexyl carbamate,di-1-methyl-2-methacryloxyethyl-hexamethylene dicarbamate,di-1-methyl-2-methacryloxyethyl-trimethylhexamethylene dicarbamate,di-1-methyl-2-methacryloxyethyl-dimethylbenzene dicarbamate,di-1-methyl-2-methacryloxyethyl-dimethylcyclohexane dicarbamate,methylene-bis-1-methyl-2-methacryloxyethyl-4-cyclohexyl carbamate,di-1-chloromethyl-2-methacryloxyethyl-hexamethylene dicarbamate,di-1-chloromethyl-2-methacryloxyethyl-trimethylhexamethylenedicarbamate, di-1-chloromethyl-2-methacryloxyethyl-dimethylbenzenedicarbamate, di-1-chloromethyl-2-methacryloxyethyl-dimethylcyclohexanedicarbamate,methylene-bis-1-chloromethyl-2-methacryloxyethyl-4-cyclohexyl carbamate,2,2′-bis(4-methacryloxyphenyl)propane,2,2′-bis(4-acryloxyphenyl)propane,2,2′-bis[4(2-hydroxy-3-methacryloxy-phenyl)]propane,2,2′-bis[4(2-hydroxy-3-acryloxy-phenyl) propane,2,2′-bis(4-methacryloxyethoxyphenyl)propane,2,2′-bis(4-acryloxyethoxyphenyl)propane,2,2′-bis(4-methacryloxypropoxyphenyl)propane,2,2′-bis(4-acryloxypropoxyphenyl)propane,2,2′-bis(4-methacryloxydiethoxyphenyl)propane,2,2′-bis(4-acryloxydiethoxyphenyl)propane,2,2′-bis[3(4-phenoxy)-2-hydroxypropane-1-methacrylate]propane,2,2′-bis[3(4-phenoxy)-2-hydroxypropane-1-acrylate]propane, propoxylated(2) neopentylglycol diacrylate (Sartomer SR9003), isobornyl methacrylate(Sartomer SR423), aromatic acrylate oligomer (Sartomer CN137), aliphaticallyl oligomer (Sartomer CN9101), dimethylaminoethyl methacrylate(DMAEMA), methylene bisacrylamide (MBA),dimethylaminopropylmethacrylamide,methacrylamido-propyltrimethylammonium chloride, and the like. Allproducts designated herein by reference to “Sartomer” and product numberare available from Sartomer Company, Inc. (Exton, Pa.).

Other polymerizable resins suitable for use in the first componentinclude acrylamide, methylene bis-acrylamide, methylenebis-methacrylamide, diacetone/acrylamide diacetone methacylamide,N-alkyl acrylamides, and N-alkyl methacrylamides where alkyl is a lowerhydrocarbyl unit. Other suitable examples of polymerizable resins caninclude polymerizable groups selected from isopropenyl oxazoline, vinylazalactone, vinyl pyrrolidone, styrene, divinylbenzene, urethaneacrylates, urethane methacrylates, polyol acrylates, and polyolmethacrylates.

In certain embodiments, the first component can include suitablepolylactic acid (D and L), polyglycolic acid, polylactic/polyglycolicacid copolymers, vinyl group containing polyesters such aspolypropylenefumarate and polypropyleneitaconate, polydioxane,poly(ε-caprolactone), poly(valerolactone), poly(trimethylene carbonate),poly(tyrosine-carbonates) and poly(tyrosine-arylates), poly(iminocarbonates), poly(hydroxybutyrate) (PHB), poly(hydroxyvalerate),poly(tartonic acid), poly (β-malonic acid), polyhydroxycarboxylic acids,polybutyrene succinate, polybutylene adipate, aliphatic disisocyanatebased polyurethanes, peptide-based polyurethanes, polyester orpolyorthoester based polyurethanes, polyphosphazenes incorporating aminoacid ester, glucosyl, glyceyl, lactate or imidazolyl side groups,collagen, chitosan, alginate, cellulose, starches, sugars, polypeptides,polyethylene glycol, vinyl pyrrollidones, acrylamides and methacrylatesor any of their derivates or copolymers, or a copolymer micellecomprising copolymer of polyethylene oxide (PEO), polypropylene oxide(PPO), polyvinylpyridine (PVP), and polystyrene (PS), such as, forexample, the triblock copolymer PEO-PPO-PEO, PPO-PEO-PPO, PVP-PS-PVP,PS-PVP-PS, PS-PEO-PS, or PEO-PS-PEO. In certain preferred embodiments,the first component comprises a resorbable material that is flowable atroom temperature comprising polymerizable functional groups, such asvinyl group containing polyesters such as polypropylenefumarate andpolypropyleneitaconate.

Preferred polymerizable resins suitable for use in the first componentinclude a Michael addition polymerizable or a cationically (e.g.,carbocationically) polymerizable group and an oxygen-containing ring.Thus, preferred polymerizable resins include epoxides, oxetanes,oxolanes, C3-C8 cyclic acetals, C3-C12 lactams, C3-C12 lactones, andC5-C20 spirocyclic compounds that contain oxygen atoms in their rings.

Particularly preferred polymerizable resins suitable for the firstcomponent include epoxy resins, which feature an oxygen-containingepoxide ring. Exemplary epoxy resins are epoxy acrylates or epoxymethacrylates. Epoxy resins can include monomeric epoxides, polymericepoxides, and combinations thereof. Epoxy resins can be aliphatic,cycloaliphatic, aromatic, or heterocyclic. Suitable polymeric epoxidesinclude linear polymers having terminal epoxy groups (e.g., a diglycidylether of a polyoxyalkylene glycol), polymers having skeletal oxiraneunits (e.g., polybutadiene polyepoxide), and polymers having pendantepoxy groups (e.g., a glycidyl methacrylate polymer or copolymer).

Epoxides can be pure compounds or may be mixtures containing one, two,or more epoxy groups per molecule. The “average” number of epoxy groupsper molecule is determined by dividing the total number of epoxy groupsin epoxy-containing material by the total number of epoxy moleculespresent. Epoxides used in the first compound can have, for example, anaverage of at least 1 polymerizable epoxy group per molecule, andpreferably an average of at least about 1.5 polymerizable epoxy groups,and more preferably an average of at least about 2 polymerizable epoxygroups.

Accordingly, preferred suitable polymerizable resins for the firstcomponent include non-alkoxylated trimethylpropane tri(meth)acrylate(non-alkoxylated TMPT(M)A), alkoxylated trimethylolpropanetri(meth)acrylate (alkoxylated TMPT(M)A) (e.g., ethoxylated (15)TMPT(M)A, ethoxylated (9) TMPT(M)A, ethoxylated (6) TMPT(M)A,ethoxylated (3) TMPT(M)A, propoxylated (3) TMPT(M)A, and propoxylated(6) TMPT(M)A), epoxy acrylate, modified epoxy acrylate (e.g., SartomerCN115), bisphenol A epoxy methacrylate oligomer (Sartomer CN-151),aliphatic acrylate modifier (Sartomer MCURE 201 and Sartomer MCURE400),glycerol polyglycidyl ether, glycidyl acrylate, glycidyl acrylate ofbis-phenol A and the diglycidyl methacrylate of bis-phenol A (bis-GMA),propoxylated (5) glycerol ethoxylated bisphenol-A-triacrylate, (6)ethoxylated (2) bisphenol A diacrylate (E(2)BisDA), and ethoxylated (4)bisphenol A diacrylate (E(4)BisDA)). Useful epoxy-containing materialsalso include those which contain cyclohexene oxide groups such as theepoxycyclohexanecarboxylates, typified by3,4-epoxycyclohexylmethyl-3,4-epoxycyclohexanecarboxylate,3,4-epoxy-2-methylcyclohexylmethyl-3,4-epoxy-2-methylcyclohexanecarboxylate, and bis(3,4-epoxy-6-methylcyclohexylmethyl) adipate. For amore detailed list of useful epoxides of this nature, see U.S. Pat. No.3,117,099, which is specifically incorporated herein by reference in itsentirety.

Additionally, preferred suitable polymerizable resins of the firstcomponent include (i) glycidyl esters of neodecanoic acid (ERISYSGS-110) and Linoleic Acid dimer (ERISYS GS-120) (both from CVC SpecialtyChemicals, Moorestown, N.J.), other glycidyl esters (including thosesupplied by Aldrich, St. Louis, Mo.) such as diglycidyl stearate,diglycidyl azelate, diglycidyl pimelate, diglycidyl adipate, diglycidylsuccinate, diglycidyl oxalate, and olyglycidyl(meth)acrylate, and thelike, (ii) glycidyl ethers such as poly[(phenyl glycidylether)co-formaldehyde], N,N-diglycidyl-4-glycidyloxyaniline ether,neopentyl glycol diglycidyl ether; Bisphenol A diglycidyl ether,Bisphenol A propoxylate (1 PO/phenol) diglycidyl ether, AraLdite GY 281(Bisphenol F epoxy resin with moderate viscosity), ARALDITE 506(Bisphenol A epoxy resin), (AraLdite products are from Huntsman,Woodlands, Tex.), castor oil triglycidyl ether (ERISYS GE-35), sorbitolpolyglycidylether (ERISYS GE-60), trimethylpropane triglycidyl ether(ERISYS GE-30), 1,6-hexanediol diglycidyl ether (ERISYS GE-25),cyclohexanedimethanol diglycidyl ether (ERERISYS GE-22), 1,4-butanedioldiglycidyl ether (ERISYS GE-21), (all ERISYS™ resins are supplied fromCVC Specialty Chemicals (Moorestown, N.J.), trimethylolethanetriglycidyl ether, (1,4-butanediol diglycidyl ether), dibromo neopentylglycol diglycidyl ether, neopentyl glycol diglycidyl ether,ethyleneglycol doglycidyl ether, polyglycidyl methacrylate, polyglycidylacrylate, polyglycidylmethacrylate, polyglycidylacrylate, EPON™ 8111 (amultifunctional unsaturated epoxy resin supplied by Hexion SpecialtyChemicals, Columbus, Ohio and formed by reacting less than 50% w/wbisphenol-A-(epichlorhydrin) epoxy resin (average molecular weight<=700) with more than 50% w/w trimethylpropane triacrylate) and thelike, (iii) ester containing glycidyl ether groups such as Cyracure™ UVR6105 (3,4-epoxycyclohexylmethyl-3,4-epoxycyclohexane) from Dow-UnionCarbide Corp (Danbury, Conn.), and the like, (iv) carbonate containingglycidyl ether groups such as DECHE-TOSU (oxirane-spiroorthocarbonate)from Midwest Research Institute (Kansas City, Mo.).

Certain preferred suitable polymerizable resins for the first componentfeature an oxygen containing ring (e.g., an epoxide) and an acrylatemoiety (e.g., acrylate, methacrylate) that are covalently linked and inclose proximity to each other as depicted in the structure of Formula 1.

For example, in the structure of Formula 1, the acrylate and the oxygencontaining ring structure are separated by the covalent linkage groupR¹. R¹ can be a C₆-C₂₀ aromatic group, a C₁-C₂₀ aliphatic group, aC₃-C₁₆ cyclic group, a polymeric group, or a dendritic group. Inaddition, R¹ can contain one or more polymerizable groups such asepoxides and other suitable oxygen containing rings, ethylenicunsaturated double bonds, and the like. Preferably R¹ is any group thatdoes not interpose more than 1, 2, 3, 4 or 5 atoms in the shortestcovalent linkage between the acrylate and the oxygen containing ringstructure. R² and R³ represent any substituents capable of formingoxygen containing ring structures. Typically R² and R³ are eachindependently selected from CR′R″, C═O, O(C═O), NR′, and O, wherein R′and R″ are each independently selected from the group consisting of H,C₁-C₁₂-alkyl, C₃-C₁₀-cycloalkyl, Cl, Br, and OH. When R¹, R² and R³ areeach CH₂, the structure of Formula 1 represents glycidyl methacrylate(GMA) polymerizable resin.

The polymerizable resin of the first component can include one or morematerials that vary from low molecular weight monomeric materials tohigh molecular weight polymers. The polymers may vary greatly in thenature of their backbone and substituent groups. For example, thebackbone may be of any type and substituent groups thereon can be anygroup that does not substantially interfere with radical or cationiccuring at room temperature or body temperature. Permissible substituentgroups can include halogens, ester groups, ethers, sulfonate groups,siloxane groups, nitro groups, phosphate groups, and the like. Themolecular weight of the epoxy-containing materials can vary from about20 daltons to about 100,000 daltons, preferably from about 140 daltonsto about 30,000 daltons.

The polymerizable resin of the first component can be copolymerized withadditional acrylates. For example, when the first component includes anepoxide resin such as GMA, the cement product may also include a secondpolymerizable resin for copolymerization. Such co-polymerizable resinsinclude methyl methacrylate, ethyl methacrylate, propyl methacrylate,and higher methacrylates, acrylates, ethacrylates, and similar species.Other types of copolymerizable material include epoxide compounds,polyurethane-precursor species, and a wide host of other materials.Still other examples of copolymerizable monomers that can be used in thecement product include methyl-, ethyl, isopropyl-, tert-butyloctyl-,dodecyl-, cyclohexyl-, chlorolethyl-, tetrachloroethyl-,perfluorooctyl-hydroxyethyl-, hydroxypropyl-, hydroxybutyl-,3-hydroxyphenyl-, 4-hydroxphenyl-, aminoethyl-, aminophenyl-, andthiophenyl-substituted acrylate, substituted methacrylate, substitutedethacrylate, substituted propacrylate, substituted butacrylate, andsubstituted chloromethacrylate, as well as the homologous mono- anddi-(meth)acrylic acid esters of bisphenol-A, dihydroxydiphenyl sulfone,dihydroxydiphenyl ether, dihydroxybiphenyl, dihydroxydiphenyl sulfoxide,and 2,2-bis(4-hydroxy-2,3,5,6-tetrafluorophenyl)propane. Additionalcopolymerizable monomers capable of sustaining a polymerization reactioninclude di-, tri-, and higher ethylene glycol acrylates such as ethyleneglycol dimethacrylate, diethylene glycol dimethacrylate, trimethyleneglycol dimethacrylate, trimethylol propane trimethacrylate, and thelike. In some cases, mixtures of two, three, and more polymerizablespecies can be combined to good effect.

The second component of the cement product includes a compoundcomprising more than one type of amine selected from the groupconsisting of a primary amine, a secondary amine, a tertiary amine, anda quaternary amine. Suitable compounds for the second component includenaturally occurring polyamines (such as those from humus), aliphaticpolyamines, aromatic polyamines, or mixtures thereof. Polyamines thatcan be used in the second component include phenylenediamine,ethylenediamine, triethylenetetraamine, and a wide variety of otheraliphatic and aromatic diamines that polymerize when mixed with thepolymerizable resin of the first component. Suitable compounds for thesecond component include modified polyamino acids such as polylysinesand imidazole-modified polylysines. Suitable polyamines can includebranched dendrimers with multiple types of amines, such aspolyamidoamine (PAMAM) dendrimers.

Sterically hindered functional groups in the second component can beused to lengthen working time. For example, the inclusion of stericallyhindered amine functional groups (e.g., secondary amines) can lengthenset time. Furthermore, working times can be lengthened by using lowermolecular weight second component compounds.

Additional amine-containing compounds suitable for inclusion in thesecond component include monomers or oligomers further comprising ester,ether, amide, carbonate, urethane, or oxirane functional groups on theside chain or main chain. Preferred groups on the side chain or mainchain include imide, imidine and isocyanate groups. Suitableamine-containing compounds of the of the second component can include,for example, oleylamine, stearylamine, 2-ethylhexylamine,ethylenediamine, propylenediamine, 1,6-hexamethylenediamine,aminoethanolamine, ethanolamine, propylenetriamine, butylenetriamine,diethylenetriamine, triethylenetetramine, tetraethylenepentamine,N-(3-aminopropyl)-1,3-propanediamine, pentaethylenehexamine,menthanediamine, isophoronediamine, xylenediamine,tetrachloro-p-xylenediamine, methylenedianiline, diaminodiphenylsulfone,polyaniline, N-methylpiperazine, hydroxyethylpiperazine, piperidine,pyrrolidine, morpholine, diethanolamine, streptidine, stilbamidine,2-deoxystreptamine, dapsone, p-diaminoazobenzene, 4,4′-diaminodiphenylether, and the like. Preferred suitable amine-containing compounds ofthe second component can include DYTEK A™(2-methyl-1,5-pentamethylenediamine), DYTEK EP™(2-ethyl-1,3-trimethylenediamine), DYTEK DCH-99™ (o-cyclohexanediamine),and m-phenylenediamine and naturally occurring polyamines such as1,4-diaminobutane (putrescine), spermidine, and spermine.

Still other amine-containing compound suitable for use in the secondcomponent include biological amines such as guanidine, uracil, thymine,adenine, guanine, cytosine, xanthine, and their respective biologicalnucleotides or derivatives thereof. Exemplary derivative nucleotidesinclude 2,4-diamino-6-hydroxy-pyrimidine and 2,6-diaminopurine. Thesecond component can include oligomers, polymers and copolymers of aminoacids such as phenylalanine, tryptophan, arginine, tyrosine, cysteine,or lysine.

In addition to the compounds described herein, the second component canfurther include free amino acids, such as, phenylalanine, tryptophan,arginine, tyrosine, cysteine, or lysine. For example, amino acids can beblended with or grafted to (e.g., by heating together with) polyaminesof the second component. The addition of amino acids can lower themelting point of and render the second component liquid at roomtemperature. Thus, addition of amino acids to the second component canenhance the handling properties of the cement compositions of theinvention. Additionally or alternatively, the addition of amino acidscan enhance the curative hardening reaction of the first and secondcomponents.

In some embodiments, the invention provides a slowly resorbable ornon-resorbable cement product with a second component that includes anaturally occurring polyamine. For example, a slowly resorbable ornon-resorbable cement product can comprise (i) a first component thatincludes Epon 811™ (e.g. about 100% (w/w)) or a mixture of bisphenol Adiglycidyl ether (e.g., about 0-75% or, preferably, 33-67% (w/w)) andtrimethylolpropane triacrylate (e.g., about 0-75% or, preferably, 33-67%(w/w)) and (ii) a second component that includes a mixture of spermidine(e.g., about 0-75% or, preferably, 0-33% (w/w)) and, optionally, Dytek A(about 0-67% w/w). Another naturally occurring polyamine can be usedinstead of some or all of the spermidine in the second component. In theforegoing exemplary slowly resorbable or non-resorbable cement product,the ratio of first component to second component can be about 0.8:1,about 1:1, or about 1:1.2 (mole equivalent:mole equivalent) In theforegoing exemplary slowly resorbable or non-resorbable cement product,the ratio of first component to second component can be 1:0.999 (moleequivalent:mole equivalent).

In other embodiments, the invention provides a resorbable cement productwith a second component that includes a naturally occurring polyamine.For example, a resorbable cement product can comprise (i) a firstcomponent that includes one or more of the following compounds: sorbitolpolyglycidyl ether (e.g., about 0-60% or about 0-40% (w/w)),trimethylolpropane triacrylate, (e.g., about 0-50% or about 0-30% (w/w))and/or, 1,4-butanediol (e.g., about 0-40% or about 0-20% (w/w)) and (ii)a second component that includes a spermidine (e.g., about 20-100% w/w)and, optionally, Dytek A™ or Dytek EP™ (e.g., about 0-80% w/w). In thefirst component, 1,6-butanediol or trimethylolpropane benzoatediacrylate can be used instead of some or all of the 1,4-butanediol; andanother naturally occurring polymanime can be used instead of some orall of the spermidine in the second component. In such an example, theratio of first component to second component can be 0.8:1; 1:1; 1:1.2(mole equivalent:mole equivalent). The ratio of first component tosecond component can be 1:0.999 (mole equivalent:mole equivalent).

Suitable amine-containing compounds of the second component can alsoinclude polyalkyleneamines and derivatives thereof, such aspolyethyleneimine (PEI) and PEI derivatives, and polypropyleneimine(PPI) and PPI derivatives, which typically include primary, secondaryand tertiary amines. The PEI or PEI derivative can also includequaternary amines. PEI derivatives include ethoxylated PEI,hydroxyethoxylated PEI, and hydroxypropylated PEI. The PEI or PEIderivatives can be branched or linear. Preferably, the PEI or the PEIderivative has a sufficiently low molecular weight that it is a liquid.For example, the PEI or PEI derivative can have an average molecularweight of less than about 200 kDa, less than about 150 kDA, less thanabout 100 kDa, less than about 90 kDa, less than about 80 kDa, less thanabout 70 kDa, less than about 60 kDa, less than about 50 kDa, less thanabout 40 kDa, less than about 30 kDa, less than about 25 kDa, less thanabout 20 kDa, less than about 15 kDa, less than about 10 kDa, less thanabout 5 kDa or less than about 2 kDa. The PEI or PEI derivative can havean average molecular of less than about 2 kDa and more than about 0.2Kda. Preferably, the PEI or PEI derivative has an average molecularweight of less than about 1 kDa and greater than about 0.3 kDa.

It has been found that the concentration of primary amines in PEIcorrelates with faster set times for certain cement products of theinvention. For example, branched PEI with a molecular weights of 800 Daand linear PEI with a molecular weight of 423 Da, which have relativelyhigh concentration of primary amines (i.e., on their chain-ends), havebeen found set faster than PEI with molecular weight of 10 kDa or 1.8kDda in cement products of the invention. Thus, preferred cementproducts of the invention can include PEI and PEI derivatives havingaverage molecular weights of about 800 Da to about 400 Da. Such productshave been found to exhibit set times of about 5-15 minutes and harden inless than an hour, e.g., in about 30 minutes.

In combination with a first component compound, branched PEI, branchedPPI, and dendrimers containing tertiary amines can be particularlyuseful for their catalytic effect, which shortens dough time and settime and produces no more than a moderate exothermic temperatureincrease, if any.

In another embodiment, the second component includes a compound with amercapto (SH—) group, a hindered amine or dimethylthiotoluenediamine(DMTDA). Generally, mercapto group containing compounds includemercaptouracil, polycysteines, diethoxymethane polysufides.Diethoxymethane polysufides include compositions with (i) at least about0.5%, 0.8%, or 1% mercaptans and no more than about 2%, about 3%, about5% or about 7.7% mercaptans and (ii) a molecular weight of at leastabout 750, about 1,000, or about 2,000 and no more than 3,000, 4,000,7,000 or 10,000. Such diethoxymethane polysufides include LP2, LP3,LP23, LP33, LP55, LP56 and LP980 available from Morton International(Woodstock, Ill.), and the like. Mercapto group-containing compounds canbe used in their pure form or in combinations as nucleophiles to bereacted with (meth)acrylate type enone functional resins. Hinderedamines include sterically hindered amines, which are substituted on theN-atom by, for example, an alkyl, an alkoxy or a cycloalkoxy moiety.Sterically hindered amines include biocompatible formulations ofsterically hindered amines disclosed in U.S. Pat. Nos. 5,204,473, and6,906,113, incorporated herein by reference in their entirety. Hinderedamines also include polyaspartate and related compounds offered by BayerMaterial Sciences (Pittsburgh, Pa.) with the trade name of Desmophen™(e.g., Desmophen NH 142). Hindered amines and DMTDA compositions, suchas those offered by Albemarle (Baton Rouge, La.) under the trade nameEthacure™ 300 and Ethacure™ 100 are suitable for use in the additionpolymerization systems for (meth)acrylates, di-, tri or polyepoxides aswell as di-, tri or polyisocyanates.

Optionally, any one of the embodiments of the cement products disclosedherein can further include a third component comprising a compoundcomprising an oxygen-containing ring. The oxygen-containing ring can beany suitable oxygen-containing ring, for example, any oxygen containingring described herein. Typically the oxygen-containing ring is selectedfrom epoxides, oxetanes, oxolanes, C3-C8 cyclic acetals, C3-C12 lactams,C3-C12 lactones, and C5-C20 spirocyclic compounds that contain oxygenatoms in their rings.

Desirably the ratio of equivalents of acceptor hydrogen to equivalentsof donor hydrogen is from about 0.5:1 to about 1:0.5, preferably about0.75:1 to about 1:0.75, more preferably about 0.9:1 to about 1:0.9, andmost preferably about 1:1. The equivalents of acceptor hydrogen is theaverage molecular weight of all compounds in the first and optionalthird components comprising polymerizable groups (e.g., ethylenic doublebond groups, oxygen-containing ring groups) divided by the total numberof acceptor hydrogen groups. The equivalents of donor hydrogen can becalculated as the average molecular weight of all compounds comprisingamine groups (in the second component) divided by the total number ofdonor hydrogen groups. For example, the “donor” hydrogen equivalentweight in the amine functionality of PET is 43 Da while the “acceptor”ethylenic unsaturated double bond or oxygen containing ring on GMAmonomer (molecular weight is 142 Da), the equivalent weight of eachacceptor functionality is 72 Da.

Optionally, any one of the embodiments of the cement products disclosedherein can further include mixing a filler with the additional first,second, and optional third component of the cement product. The fillercan be inert, or alternatively the filler can be comprised by thebioactive component described herein. Inert fillers include glassfillers, such as CORTOSS™ from OrthoVita (Malvern, Pa.) that have goodstrength characteristics. Bioactive components are useful for promotingbone tissue growth around the restorative cement and, preferably, bonetissue ingrowth into the cement. In addition, the bioactive componentcan serve as a stiffening and strengthening agent for the cementproduct. Representative documents describing such materials include U.S.Pat. Nos. 2,920,971, 3,732,087, 3,981,736, 4,652,534, 4,643,982,4,775,646, 5,236,458, 5,336,642, 5,681,872, and 5,914,356, as well asBrown, W. F., “Solubilities of Phosphate & Other Sparingly SolubleCompounds,” in Environmental Phosphorous Handbook, Ch. 10 (1973). All ofthe foregoing patents and reference documents are incorporated herein byreference.

Typically the bioactive component includes a bioactive glass ceramics,Bioglass™ (sold by NovaBone), Cervital™, water-soluble glasses,collagen, grafted bone material such as allografts, autografts, andxenografts, calcium phosphate ceramics, or any other bioactive materialknown to promote bone tissue formation. The bioactive component caninclude known bioactive materials such as densified and microporoushydroxyapatite, fluorapatite, oxyapatite, wollastonite,apatite/wollastonite glass ceramics, anorthite, calcium fluoride,calcium sulfate, agrellite, devitrite, canasite, phlogopite, monetite,brushite, octocalcium phosphate, whitlockite, cordierite, berlinite,combeite, tetracalcium phosphate, tricalcium phosphate (TCP)(e.g., α-and β-tricalcium phosphates), amorphous calcium phosphate, dicalciumphosphate, phosphoric acid crystals, disodium hydrogen phosphate, andother phosphate salt-based bioceramics. Preferably the bioactivecomponents are particles that are fully dense having no internalmicroporosity (lacking percolated micro-boundary layers or micro-voids),a particle size of 0.5 microns or more and 100 microns or less (e.g.,about 80 microns or less, about 50 microns or less, or about 30 micronsor less), and a surface area of about 50 m²/g or less, about 25 m²/g orless, about 10 m²/g or less, about 5 m²/g or less, or about 2.5 m²/g orless. The particle size distribution can be broad, bimodal, orpreferably trimodal, which can be less than about 500 microns, with lessthan about 10% by weight being sub 0.5 microns sized.

Fillers suitable for use in the cement products of the invention caninclude other bioceramics, graphite, pyrolytic carbon, bone powder,demineralized bone powder, anorganic bone from which organicconstituents have been removed and consists mainly of bone mineralmaterial, dentin tooth enamel, aragonite, calcite, nacre,hydroxyapatite, and other calcium phosphate materials. Fillers can alsoinclude carbon, collagen, tendon or ligament derived tissue, keratin,cellulose, hydroxyapatite and other calcium phosphates. Generally,fillers can comprise from about 0.1% to about 95% by weight of thecement product prior to mixing.

Fillers can also include resorbable polyester fillers comprised of PGA,PLGA, PLLA, etc. These microspheres will hydrolyze and resorb therebycreating porosity to facilitate tissue ingrowth. Generally, these fillercan be spherical to whisker-like tin morphology, 10 nm to 5 mm inparticle size and comprised from about 0.1% to about 95% by weight ofthe cement product prior to mixing.

In some embodiments, the bioactive component is surface modified withone or more coupling groups. Suitable coupling groups can include, forexample, alkoxysilanes containing epoxide, amine, or vinyl groups,organic isocyanates, acrylic acids, methacrylic acids, polyacrylicacids, citric acids, zirconates, titanates, diamines, amino acids, andpolypeptides.

Other coupling groups for modifying the surface of the bioactivecomponent include silane coupling agents, bisphosphonates and theirderivatives, pamidronic acid and salts thereof (e.g., disodium salts),phytic acid, and the like.

In some embodiments, the filler includes one or more of the followingbiocompatible binders: fibrin glue, fibrinogen, thrombin, musseladhesive protein, silk, elastin, collagen, casein, gelatin, albumin,keratin, chitin or chitosan, cyanoacrylates, epoxy-based compounds,dental resin sealants, dental resin cements, glass ionomer cements suchas IONOCAP™ and INOCEM™ (Ionos Medizinische Produkte GmbH, Greisberg,Germany), gelatin-resorcinol-formaldehyde glues, collagen-based glues,cellulosics such as ethyl cellulose, bioabsorbable polymers such asstarches, polylactic acid, polyglycolic acid, polylactic-co-glycolicacid, polydioxanone, polycaprolactone, polycarbonates, polyorthoesters,polyamino acids, polyanhydrides, polyhydroxybutyrate,polyhyroxyvalyrate, poly (propylene glycol-co-fumaric acid),tyrosine-based polycarbonates, pharmaceutical tablet binders (such asEUDRAGIT™ binders available from Huils America, Inc.),polyvinylpyrrolidone, cellulose, ethyl cellulose, micro-crystallinecellulose and blends thereof, starch ethylenevinyl alcohols,polycyanoacrylates, polyphosphazenes, nonbioabsorbable polymers such aspolyacrylate, polymethyl methacrylate, polytetrafluoroethylene,polyurethane, polyamide, and the like. Preferred binders arepolyhydroxybutyrate, polyhydroxyvalerate and tyrosine-basedpolycarbonates.

Additionally, fillers can include (i) calcification-controlling agents,such as, dimethyl sulfoxide (DMSO), surfactants, diphosphonates,aminooleic acid, and metallic ions, for example, iron and aluminum ions,(ii) plasticizers, such as, liquid polyhydroxy compounds, which includemonoacetin, diacetin, and, preferably, glycerol or an aqueous solutionof glycerol, (iii) thixotropic thickeners, such as, solutions includingpolyvinyl alcohol, polyvinylpyrrolidone, cellulosic ester (for example,hydroxypropyl methylcellulose), carboxy methylcellulose, pectin, xanthangum, food-grade texturizing agent, gelatin, dextran, collagen, starch,hydrolyzed polyacrylonitrile, hydrolyzed polyacrylamide, polyelectrolyte(for example polyacrylic acid salt), hydrogels, and chitosan. Othermaterials suitable for suspending particles can also be combined with awetting agent in an amount sufficient to significantly improve thesuspension characteristics of each compositions described herein (i.e.,a first, second, third, or filler composition), alone or in combinationwith another composition described herein.

Preferred fillers include leachable inorganic salts such as sodiumchloride, magnesium chloride, calcium sulfate, and calcium carbonate.Other fillers include lithium chloride, lithium bromide, sodium bromide,potassium chloride, potassium bromide, rubidium chloride, cesiumchloride, lithium iodide, sodium iodide, potassium iodide, rubidiumiodide, cesium iodide, rubidium bromide, cesium bromide, lithiumsulfate, lithium nitrate, lithium nitrite, lithium phosphate, lithiumcyanide, lithium carbonate, sodium sulfate, sodium nitrate, sodiumphosphate, sodium cyanide, sodium carbonate, potassium sulfate,potassium nitrate, potassium phosphate, potassium cyanide, potassiumcarbonate, lithium acetate, lithium benzoate, lithium octanoate, lithiumstearate, lithium salicylate, lithium oxalate, sodium acetate, sodiumoleate, sodium benzoate, potassium acetate, potassium oleate, potassiumlactate, alkali metal salts of phenols such as lithium phenolate,lithium resorcinolate, bisphenol A lithium salt, sodium phenolate,potassium phenolate, sodium methylate, lithium methylate, sodiumethylate, potassium ethylate (and other methylates, ethylates, oralkylates), calcium oxide, magnesium oxide, beryllium oxide, zinc oxide,silicon oxide, carbonates such as ammonium carbonate, barium carbonate,strontium carbonate, hydroxides such as sodium hydroxide, potassiumhydroxide, magnesium hydroxide, barium hydroxide, nitrousoxide-activated carbon, ammonia-activated carbon, ammonium thiocyanate,sodium thiocyanate, potassium thiocyanate, magnesium thiocyanate,potassium thiocyanate, zinc thiocyanate, manganese thiocyanate,triethylamine hydrochloride, 2,4,6-tris(dimethylaminomethyl)phenol2-ethylhexanoate, laurylamine acetate, 1,8-diazabicyclo[5,4,0]undecene-7phenolate, laurylamine acetate, and the like.

Certain preferred fillers include microspheres (˜100 micrometer), sugarssuch as sorbitol, and mannitol, and water soluble polymers such aspolyacrylic acid, polyvinyl alcohol and its copolymers with polyvinylacetate, polyvinylpyrrolidone, and the like. For some applications,preferred water soluble polymers are those that can be controllablyresorbed or released into body fluid and, thus, create a pore structureinto which bone tissue can grow.

Fillers for use in conjunction with the cement products of the inventionalso include bovine bone powder or bovine demineralized bone particles.

In other further embodiments, the filler can include biological and/orpharmaceutical agents to enhance and accelerate bone formation such asBMP's, bisphosphonates, gene delivery vectors (promoting osteogenesis orpreventing osteolysis), stem cells (stem cell can engineered by genedelivery vectors to upregulate expression of desired proteins such asBMP's), antibiotics, pain killers, etc. The biological additive can beany suitable biological additive, for example plasmid DNA or RNA orproteins (e.g., bone morphogenetic proteins 2, 4, 7). The pharmaceuticaladditive can be any suitable pharmaceutical additive, for examplebisphosphonates (e.g., alendronate) and cis-platinum, antibiotics,anti-inflammatories, anti-arthritism, erythropoeitin, and the like.

Biological or bioactive agents that can be combined with fillers includecollagen and insoluble collagen derivatives (which can be combined, forexample, with bovine bone powder or demineralized bone particles).Exemplary collagen and collagen derivatives include those disclosed inU.S. Pat. Nos. 5,824,331, 5,830,492, 5,834,005, 6,231,881, 6,261,587,6,352,707, and 7,303,814 as well as in U.S. Application Publication Nos.20030232746 and 20050118230A1, some of which are sold under the tradename E-Matrix™ by the Encelle Division of Pioneer SurgicalOrthobiologics (Greenville, N.C.). Each of the foregoing patents andpublished applications are incorporated by reference herein in theirentirety. Additional biological or bioactive agents that can be combinedwith fillers include amino acids, peptides, vitamins, inorganicelements, co-factors for protein synthesis, hormones, endocrine tissueor tissue fragments, synthesizers, enzymes (such as collagenase,peptidases, oxidases, and the like), polymer cell scaffolds withparenchymal cells, angiogenic agents and polymeric carriers containingsuch agents, collagen lattices, antigenic agents, cytoskeletal agents,cartilage fragments, living cells such as chondrocytes, bone marrowcells, mesenchymal stem cells, natural extracts, genetically engineeredliving cells or otherwise modified living cells, and tissue transplants.Still other biological agents include autogenous tissues (such as blood,serum, soft tissue, and bone marrow), bioadhesives, osteoinductivefactor, fibronectin (FN), endothelial cell growth factor (ECGF),cementum attachment extracts (CAE), ketanserin, human growth hormone(HGH), animal growth hormones, epidermal growth factor (EGF),interleukin-1 (IL-1), human alpha thrombin, transforming growth factor(TGF-beta), insulin-like growth factor (IGF-1), platelet derived growthfactors (PDGF), fibroblast growth factors (FGF, bFGF, and the like),periodontal ligament chemotactic factor (PDLGF), somatotropin, bonedigestors, antitumor agents, immunosuppressants, permeation enhancers(e.g., fatty acid esters such as laureate, myristate and stearatemonoesters of polyethylene glycol, enamine derivatives, alpha-ketoaldehydes), and nucleic acids.

Fillers can also, optionally, include a biostatic/biocidal agent. Forexample the filler can include one or more of the following antibioticor antimicrobial agents: erythromycin, bacitracin, neomycin, penicillin,polymycin B, tetracycline, biomycin, chloromycetin, streptomycins,cefazolin, ampicillin, azactam, tobramycin, clindamycin, and gentamicin.Other biostatic/biocidal agents include povidone, sugars such asdextran, glucose and mucopolysaccharides, and the like. Still otherbiostatic/biocidal agents include antiviricides, such as those which areeffective against HIV and hepatitis. Preferred biostatic/biocidal agentsare antibiotics.

The amount of filler added can represent from about 10 to about 95% byweight of total cement mix. For example, preferably an inert fillerrepresents from about 65% to about 85% by weight of total cement mix.Preferred densified microcrystalline and nanocrystalline bioactivehydroxyapatite, tricalcium phosphate, and bioceramic content can rangefrom about 10 to about 99% by weight, preferably less than 85% byweight, more preferably from about 35% to about 80% by weight, forexample, from about 50% to about 80% by weight of that filler.

Preferably, the bioactive component includes a nanocrystalline and/orpoorly crystalline apatite material, such as hydroxyapatite or anotherapatitic calcium phosphate. Nanocrystalline and/or poorly crystallineapatite materials have been described, for example, in U.S. Pat. Nos.6,117,456, 6,953,594, 6,013,591 (which has been reissued as U.S. ReissueNo. RE 39,196), and U.S. Pat. No. 6,972,130. The foregoing patentdocuments are incorporated herein by reference in their entirety.Nanocrystalline apatite material is also commercially available, forexample, from Angstrom Medica (Woburn, Mass.). In certain embodiments,the bioactive component includes nanocrystalline hydroxyapatite (nHA)whisker crystals. These nHA crystals can form a fibrous networkthroughout the polymerized cement that reinforces the cement undercompressive loads.

Batches of nHA whisker can be synthesized in reactors by feeding 0.167 Msolution of reagent grade Ca(NO3)2.4H2O (CaN) (Fluka Chemie AG, Buchs,Switzerland) onto a well-mixed solution of 0.100 M (NH4)2HPO4 (NHP)(Fluka) and aging for 100 hours. Production of nHA whisker can beoptimized by controlling temperature and concentration of startingmaterials. Optimal production occurs at temperatures of about 25° C. toabout 200° C., more preferably about 60° C. to about 120° C., and evenmore preferably about 80° C. to about 100° C., which allows the growthof anisotropic nHA crystals having multiple different aspect ratios thatare greater than 1. For example, batches of nHA crystals can have aspectratios (length:diameter) ranging from about 1.5:1 to about 1000:1, fromabout 2:1 to about 500:1, from about 3:1 to about 250:1, from about 4:1to about 200:1, from about 5:1 to about 150:1, from about 6:1 to about125:1, from about 7:1 to about 100:1, from about 8:1 to about 75:1, fromabout 9:1 to about 60:1, or from about 10:1 to about 50:1. Generally,production temperatures should not exceed the boiling point of thereaction mix. Reactant concentration can also be controlled by adjustingtemperature, i.e., by raising the temperature to remove water andthereby increase reactant concentration. For example, the reaction canbe optimized by comparing the nHA produced in a reaction after 5% waterremoval, 10% water removal, and 15% water removal. The particle size ofthese batches can be determined using laser diffraction. Surface areaand porosity measurements are obtained using nitrogen gas adsorption.Particle settling data can also be obtained. Whisker crystal size andmorphology of the hydroxyapatite are confirmed using transmissionelectron microscopy.

Following chemical precipitation and aging, the powders can be recoveredby centrifugation and washed with aqueous solvent to remove residualionic species. Subsequently, these powders can undergo a second seriesof washes with organic solvent to remove any remaining precipitationsolvent. After removing residual solvent, the resulting precipitate canbe re-suspended in an organic monomer, oligomer, or prepolymer solutionto prevent hard agglomeration or alignment of whisker particles and,thereby, produce a highly dispersed suspension of nHA whiskers that canbe used in the bioactive component of the cement product describedherein.

The nHA whiskers of a bioactive component can also be sheared intoagglomerated bundles of highly aligned whiskers of different particlesize, particle density, and porosity. The nHA powder recovered bycentrifugation can be washed as described above, except that instead ofthe final resuspension in solvent, the excess organic solvent can beremoved from the powder, and shear forces applied to allow nHA whiskersto align. Shear forces for this secondary processing technique can beapplied using a centrifuge, a pigment mixer and a planetary ball mill.

These two processing (non-sheared and sheared) preparations can producenHA whiskers having different in particle size, surface area, andporosity, all of which will influence handling and volume loading in thepolymer system, as well as the properties of the final cement productthat includes such nHA whiskers. Thus, the properties of nHA whiskerscan be optimized so that when mixed with the first and the secondcomponent of a cement product disclosed herein, the resulting cement hasthe viscosity and flowability characteristics that are appropriate forthe application in which the cement is to be used. For example, theproperties of nHA whiskers can be optimized for use in differentinjectable embodiments of the cement product of the invention. Suchinjectable embodiments include those suitable for injection duringorthopedic and dental procedures.

The first, second, and optional third component described herein and,optionally, the filler described herein desirably are selected so as toprovide a thermosetting cement product that is mildly exothermic, isisothermic, or is mildly endothermic. Therefore, the cement productdisclosed herein can be used to treat bone defects with less concern forthermal necrosis than is associated with the more exothermic restorativecements that are currently available. It has been reported that thermalnecrosis of bone tissue can occur when temperatures surpass 50° C. formore than one minute. Provenzano et al., “Bone Cements: Review of TheirPhysiochemical and Biochemical Properties in PercutaneousVertebroplasty,” Am J. Neuroradiol. 25: 1286-1290 (2004). Thus,preferably, the first component, the second component, and, optionally,the bioactive component are selected so that when the components aremixed to form a bone cement, the polymerization (i.e., cement hardening)reaction does not rise in temperature or, alternatively, produces a mildrise in temperature that is insufficient to heat the surrounding tissueto a temperature that exceeds 50° C. for more than one minute.

In certain embodiments of the cement product disclosed herein, the firstcomponent, the second component, and optionally, the third componentand/or the filler are selected so that when the components and,optionally, the filler are mixed, the resulting polymerization andcrosslinking reaction produces a rise in temperature that does notexceed 60° C., 59° C., 58° C., 57° C., 56° C., 55° C., 54° C., 53° C.,52° C., 51° C., 50° C., 49° C., 48° C., 47° C., or 46° C. for a periodof two minutes. In certain more preferred embodiments of the cementproduct disclosed herein, the first component, the second component and,optionally, the third component and/or the filler are selected so thatwhen they are mixed, the resulting polymerization reaction produces arise in temperature that does not exceed 45° C., 44° C., 43° C., 42° C.,41° C., 40° C., 39° C., 38° C., 37° C., 36° C. 35° C., 34° C., 33° C.,32° C., 31° C., or 30° C. for a period of two minutes. In certain stillmore preferred embodiments of the cement product disclosed herein, thefirst component, the second component and, optionally, the thirdcomponent and/or the filler are selected so that when the components aremixed, the resulting polymerization reaction produces a rise intemperature that does not exceed 29° C., 28° C., 27° C., 26° C., 25° C.,24° C., 23° C., 22° C., 21° C., or 20° C. for a period of one minute. Incertain most preferred embodiments of the cement product disclosedherein, the first component, the second component and, optionally, thethird component and/or the filler are selected so that when thecomponents are mixed, the resulting polymerization reaction produces arise in temperature that does not exceed 19° C., 18° C., 17° C., 16° C.,15° C., 14° C., 13° C., 12° C., 11° C., or 10° C. for a period of oneminute. The rise in temperature can be measured at room temperature(about 25° C.) or at body temperature (about 37° C.). The rise intemperature can be measured according to techniques described in, forexample, “Standard Specification for Acrylic Bone Cement” ASTM F 451-99from ASTM International (West Conshohocken, Pa.), Serbetci et al.,“Mechanical and Thermal Properties of Hydroxyapatite-Impregnated BoneCement,” 30: 543-549 (2000) and Deramond et al., “Temperature ElevationCaused by Bone Cement Polymerization during Vertebroplasty,” Bone.S25:S17-S21 (1999), which is specifically incorporated by referenceherein in its entirety.

The following theoretical considerations may be useful in the selectionof a first, second, and optional third component that, when mixed, haveoptimally low exothermic profile. Without desiring to be bound bytheory, it is believed that the components disclosed herein eachincludes material with multiple functional groups that, when mixed,participate in multiple endothermic and/or isothermic reactions thatconsume at least some of the energy generated by exothermic polymerizingreactions. In other words, the polymerization reactions of exothermicfunction groups are used at the molecular level to initiate endothermicor isothermic reactions of different reactive groups. This tandemsequence of exothermic and endothermic/isothermic reactions can beoptimized by matching the characteristic thermal zone of the exothermicfunction groups with that of the endothermic/isothermic function groups,thereby reducing or eliminating the global temperature increase of thepolymerization reaction. For example, mixing the first component and thesecond component can produce (i) mildly exothermic ring-openingreactions with the amino groups of the second component as well as (ii)carbocationic, onium formation, and/or Michael additions, which areendothermic or adiabatic. Alternatively, a mildly exothermicring-opening reaction can occur with a sulfur group ofdimethylthiotoluenediamine (DMTDA) or mercapto-containing compounds orthe hindered amine compound of a second component.

The first and second components and, optionally, the third componentand/or the filler described herein can all be selected to provide athermosetting cement product that is suitable for injection. The first,second, optional third component and optional filler can be selected toprovide the viscosity and flowability characteristics that areappropriate for the application in which the cement is to be used.Relatively low viscosity, syringable cement products (e.g., syringablepastes) are suited for filling bony defects, fracture repairs, andimplant fixations and revisions. Syringable cement products pastesshould flow to fill voids, and crevices, and adhere tightly to thesurface of the bone, tissue, or implant. Preferably, a syringable pastehas a viscosity suitable for injection through a 4-18 gauge needle,e.g., a 6-12 gauge needle. Flowability can be important for tightadherence and removal of micromotion when implant securing is beingachieved. The lack of implant motion can reduce inflammation anddetermine the success of the implant system over time. Higher viscositypastes are desirable for larger, load bearing bone defects and easilyaccessible fracture sites. A “putty” can be manipulated, sculpted andcured in place with immediate high strength capability. Oncological bonydefects are well-suited for highly loaded, highly bioactive composites.The use of hand mixed pastes of the first and second component can alsofacilitate the addition of medicaments, antibiotics, or bone growthfactors, e.g., prior to injecting or otherwise applying the pastes.

In certain embodiments of the cement product, the first, second, andoptional third components described herein and, optionally, the fillerare selected so that, when mixed, they form a cement having a desirablesetting time and/or desirable mechanical strength. Desirable settingtimes vary according to the cement's intended application. Desirablesetting times can include from about 1 to about 30 minutes (againdepending on the application). For certain injectable applicationsdesirable setting times can range from about 2 to about 25 minutes, fromabout 3 to about 20 minutes, or from about 5 to about 15 minutes.

Desirable mechanical strength will also vary according to the cement'sintended applications. Moreover, the type and amount of filler cangreatly influence one more type of mechanical strength. Desirablemechanical strength properties include the following. Compressivestrength can be from about 20 MPa to about 250 MPa. The compressivestrength typically is from about 50 MPa to about 250 MPa. Generally,compressive strength increases with the amount of filler included. Whenthe cement does not include a filler, the compressive strength can befrom about 20 MPa to about 100 MPa, e.g., typically from about 50 MPa toabout 100 MPa. When the cement includes a filler, the compressivestrength typically is from about 100 MPa to about 250 MPa. Preferablythe compressive strength is about 50 MPa or more, about 100 MPa or more,or about 150 MPa or more. A preferred tensile strength is from about 10to about 100 MPa (e.g., about 20 MPa or more, about 40 MPa or more, orabout 60 MPa or more). A preferred shear strength is from about 30 MPato about 150 MPa (e.g., about 50 MPa or more, about 80 MPa or more, orabout 110 MPa or more). A preferred flexural strength is from about 20MPa to about 100 MPa (e.g., about 30 MPa or more, about 40 MPa or more,or about 50 MPa or more). A preferred infinite compression fatigue isfrom about 20 MPa to about 150 MPa (e.g., about 40 MPa or more, about 70MPa or more, or about 100 MPa or more). A preferred tensile fatigue isfrom about 5 MPa to about 40 MPa (e.g., about 10 MPa or more, about 20MPa or more, or about 30 MPa or more). The compression modulus typicallyis in the range of about 20 MPa to about 5 GPa, preferably in the rangeof about 50 MPa to about 2 GPa. And most preferred in range of about 100MPa to about 1 GPa. The deformation percentage ranges from about 10% toabout 90%, preferably from about 20% to about 80% and most preferablyfrom about 30% to about 50%.

The different types of mechanical strengths can be measured according totests known in the art, such as ASTM F451-99a (Standard Specificationfor Acrylic Bone Cement) ASTM D695-02a (Test method for compressiveproperties of rigid plastics), ASTM C-773-88 (Standard Test Method forCompressive (Crushing) Strength of Fired Whiteware Materials), C1424-99(Standard Test Method for Monotonic Compressive Strength of AdvancedCeramics at Ambient Temperature). ASTM tests are published by ASTMInternational (West Conshohocken, Pa.).

Desirable cure and set time will also vary according to the cement'sintended applications. Cure time can refer to the time needed to achievemaximum compressive strength. Set time can refer to the time needed toachieve a dry-to-touch finish of cement. Moreover, the type and amountof filler and ratios of various components can greatly influence cureand set times. For some applications preferable set times are from about5 minutes to about 24 hours (e.g., from about 5 minutes to about 20hours, from about 5 minutes to about 12 hours, from about 5 minutes toabout 6 hours, from about 5 minutes to about 3 hours, from about 5minutes to about 1.5 hours, from about 5 minutes to about 45 minutes).Tests for determining a dry-to-touch finish (tack-free time) caninclude: ASTM C679-03 (Standard Test Method for Tack-Free Time ofElastomeric Sealants) and ASTM D2377-00(2008) Standard Test Method forTack-Free Time of Caulking.

An alternative measure of cure time is time to 50% of maximumcompression strength. For some applications, a preferable 50% strengthcure time can be up to about 20 hours (e.g., about 16 hours, about 12hours, about 8 hours, about 4 hours, about 2 hours, about 1 hours, orabout 30 minutes).

Furthermore, the preferred cement will maintain at least about 5% to100% of its initial strength (e.g. from about 5% to about 75%, fromabout 5% to about 50%, from about 5% to about 30%, from about 5% toabout 15% of initial strength) for at least about 6 months (e.g. about12 months, about 18 months, or about 24 months).

When simulated aging experiments are performed in body fluids, simulatedbody fluids, DI water, TRIS Buffer, Saline Buffer, Ringer's Lactate,Phosphate Buffer Solution with a pH from about 4 to about 8.5 on thecement, the preferred pH of the fluids when the cement is submerged inthe fluid for a minimum about 2 days (e.g., about 4 days, about 1 week,about 1 month, about 1 year) is at a pH of about 4 to about 8.5 (e.g.,from about 4 to about 8, from about 5 to about 8).

According to its application, a cement of the invention can be designedto swell when immersed in body fluids, simulated body fluids, DI water,TRIS Buffer, Saline Buffer, Ringer's Lactate, or Phosphate Buffer havingPH of from about 4 to about 8.5. The cement can be designed to swellfrom slightly more than 0% to about 500%.

The relative reactivity of functional groups in the first componenttowards functional groups of the second component can be exploited tocontrol the set time and flowability properties of cement products ofthe invention. For example, compared to glycidyl groups, acrylatefunctional groups in the first component typically react faster withprimary amines in the second component of the invention. Thus, a secondcomponent with a high ratio of primary amines typically sets morequickly when combined with a first component that includes mostlyacrylate functional groups relative to a first component that includes ahigher proportion of glycidyl groups (assuming that amine reactivegroups are not in excess of first component reactive groups). However,increasing the ratio of secondary and/or tertiary amines in the secondcomponent typically slows down the set time of a cement product thatincludes mostly acrylate functional groups in the first component, sinceacrylates are not as reactive to secondary and tertiary amines. Glycidylgroups, which are more reactive to secondary and tertiary amines, can beincluded in the first component to consume unreacted secondary and/ortertiary amines. Furthermore, since the reaction of glycidyl groups withamines is typically slower than that of acrylates with primary amines,set times can be increased by reducing the number availableacrylate-primary amine reactions and increasing the number of availableglycidyl-amine reactions in a cement product. Thus, the relative amountsof differently reactive functional groups in the cement products of theinvention can be used to control set time and flowability.

The relative reactivity of functional groups in the first componenttowards functional groups of the second component can also be exploitedto control swelling and/or resorption properties of the cement productsof the invention. Cement products that include an excess of aminefunctional groups and/or amine functional groups that are unreactivewith first component functional groups, can promote swelling and/orresorption of the cement products of the invention. Excess and/orunreacted amines from the second component can absorb water, and therebyincrease swelling of a cement product used in an aqueous or moistenvironment. Furthermore, unreacted excess amines can promotedegradation and resorption of a cement product of the invention whenplaced the body and exposed to aqueous bodily fluids.

Table 1 summarizes certain relationships between functionalitiesassociated with certain components of the invention and how theproperties of ambient temperature Michael addition reaction involvingthose functionalities. Accordingly, the relationships can be used as aguide to select a first and/or second component of the inventionsuitable for use in a particular application.

TABLE 1 POTENTIAL POTENTIAL FUNCTIONALITY ADVANTAGES DISADVANTAGESMethacrylates Higher Tg Brittle Harder Slower set Side chain hydrolyzedDistinct smell to form calcium ion Exothermic binding carboxylic acidAcrylates Flexible Lower Tg Fast set Soft Side chain hydrolyzedTriacrylate and to form calcium tetraacrylates ion binding extremelyfast set. carboxylic acid Alkoxylation: Less irritating* Lower Tg,Ethoxylate/propoxylate Hydrophilic moiety Softer finish Aliphatic esterlinkage Bioresorbable Fast hydrolysis Aromatic ester linkageBioresorbable Tend to darken Hydrophobic moiety over timeDifunctionality Good working time Sluggish for with acrylatesmethacrylates Some smell Tri-,tetra-functionality Short working timeHard finish Imine and derivatives Cationic Slight smell Phosphate binderHydrophilic Fast cure Exothermic cure Polyaniines Hard finish Smell

In some embodiments, the first, second, and third components can be aliquid or a solid at room temperatures. In preferred embodiments, thefirst, second, and third components can form upon combination flowablematerial and can be comprised of solid and/or liquid components.

The cement product of the invention can be packaged together, e.g., in akit, such that the first, second, and optional third components are notmixed until ready to use. For example, the first, second, and optionalthird components can each be packaged in a separate container.Alternatively, the first, second, and optional third components can eachbe packaged in a separate chamber of the same container, e.g., a dualchambered self-mixing syringe. More generally, syringes and otherdevices adapted for injecting cement formed from the first, second, andthird components described herein are known in the art. The bioactivecomponent can, optionally, be packaged with the first component only,with the second component only, with the third component if present,separately from each of the first, second and optional third components,or divided between two or more components.

In some embodiments, the cement product of the invention can be usedwithout chemical additives such as an initiator, a catalyst, and/or astabilizer. In other embodiments the cement product can includesignificantly smaller amounts of such additives. These embodiments canbe used to decrease the risk of chemical necrosis associated with theproduct.

In other embodiments, the cement product of the invention furtherincludes one or more additives, such as, an initiator, a catalyst,and/or a stabilizer, to optimize the working and setting times of thecement product. Such additives, which are known in the art ofrestorative cements, include heat curing catalyst and photoinitiators.For example, the cement product of the invention can further include aquinone photoinitiator in an amount ranging from about 0.01% to about10% by weight of the compound of the second component. More preferably,the quinone is present in an amount of about 0.1% to about 5% by weightof the compound of the second component. Preferred quinonephotoinitiators include alpha diketone(quinones). A more preferredquinone photoinitiator is camphoroquinone. Other photoinitiator systemsinclude a 2-benzyl-2-(dimethylamino)-4′-morpholino-butyrophenone, ormixtures of 2-hydroxyethy-2-methyl-1-phenyl-1-propanone and diphenyl(2,4,6-trimethylbenzyl) phosphine oxide. In certain embodiments, thecement product can include the appropriate relative amounts of (i)butylated hydroxytoluene (BHT) stabilizer, (ii) benzoyl peroxide (BPO)catalyst, and (iii) the compound of the second component, wherein theappropriate relative amounts are selected to optimize working time andsetting time.

Initiator or accelerator systems that can be used include those withBPO, 2,2′-Azobis (2-methylpropionitrile)(AIBN), and/or N,Ndimethyltoluidine.

The cement products of the invention can further include one or moretertiary amine containing catalysts. For example, tertiary aminecontaining catalyst can be provided with the second component. Suitabletertiary amine containing catalyst can include N,N′-dimethylpiperazine,N,N′-bis[(2-hydroxy)propyl]piperazine, N-alkylmorpholine,N,N,N′,N′-tetramethyl-1,3-butanediamine, hexamethylenetetramine,N,N-dimethylcyclohexylamine, N-alkylpiperidine,N-methyldicyclohexylamine, N-alkylpyrrolidine, tetramethylguanidine,N,N-dimethyl-p-toluidine, tri-n-butylamine, tri-2-ethylhexylamine,triamylamine, triethanolamine, 2-dimethylamino-2-hydroxypropane,tri-n-butylamine, 1-hydroxyethyl-2-heptadecylgloxysaridine,dimethylaminoethanolamine, dibutylaminoethanolamine, 2-methylimidazole,2-phenylimidazole,1,8-diaza-bicyclo[5,4,0]undecene-7,1,5-diazabycyclo[4,3,9]nonene,α-picoline, β-picoline, γ-picoline, 3,5-lutidine, purine, zanthine,naphthyridine, quinoxaline benzyldimethylamine,2-(dimethylaminomethyl)phenol, 2,4,6-tris(dimethylaminomethyl)phenol,N,N-dimethylaniline, N,N,N′,N′-tetramethyldiamino-diphenylmethane,N,N-dimethyltoluidine, tetradthylammonium iodide,lauryltrimethylammonium chloride, distearyldimethylammonium chloride,and alkylbenzyldimethylammonium chloride. Preferred tertiary aminecatalysts include triethylenediamine (or DABCO™ (Aldrich, St. Louis,Mo.)), N,N-dimethyl-p-toluidine, 1,4-Diazabicyclo[2.2.2]octane (orDABCO™ 33-LV (Aldrich)), and N,N,N′,N′-tetrakis(3-aminopropyl)-1,4-butanediamine, (DAB-Am-4 orpolypropyleneiminetetraamine dendrimer, generation 1.0 (Aldrich)). Theforegoing amines can provide a catalytic effect that shortens dough timeand set time and produces no more than a moderate exothermic temperatureincrease, if any.

Other catalysts that can be used in the cement products of the inventioninclude trimethylphosphine, triethylphosphine, triisopropylphosphine,tri-n-butylphosphine, tri-1-butylphosphine, tri-sec-butylphosphine,tris-2-ethylhexylphosphine, trioctylphosphine, trioctadecylphosphine,butyldiphenylphosphine, methylbutyloctylphosphine,dimethyloctylphosphine, triphenylphosphine, tricyclohexylphosphine,tribenzylphosphine, benzyldimethylphosphine,tris-2-phenylethylphosphine, tricyclopentylphosphine,dimethyllaurylphosphine, tritolylphosphine,tris-p-tert-butylphenylphosphine, hexamethylphosphoramide,methyltriphenylphosphonium iodide, ethyltriphenylphosphonium iodide,propyltriphenylphosphonium iodide, n-butyltriphenylphosphonium iodide,n-decyltriphenylphosphonium iodide, methyltributylphosphonium iodide,ethyltriphenylphosphonium chloride, n-butyltriphenylphosphoniumchloride, ethyltriphenylphosphonium bromide,tetrakishydroxymethylphosphonium chloride, tetraphenylphosphoniumchloride, oxazole, furazane, thiazole, and indazole.

The first, second, and optional third components can also be selected sothat when combined, the components react to form a crosslinked thermosetnetwork that is ultimately not soluble and not fusible and consumenearly all monomers and oligomers thus reducing the amount of unreactedstarting material or by-products that can leach from the formed cement.For example, in preferred embodiments, at least 80%, 85%, or 90% ofreactants are converted to into the polymer network. More preferably,95%, 96%, 97%, 98%, 99%, or 100% of reactants are converted.Additionally, the amine-containing compound of the second component inthe cement product can, in certain embodiments, reduce or eliminate theneed for a leachable free radical polymerization initiator and/or achemical accelerator such as those used in the thermoplastic PMMA bonecement products. Thus, the aforementioned advantages can reduce therisks of chemical tissue damage associated with the cement productdisclosed herein.

In another aspect, the invention provides a method of forming cement.The method includes providing the first component and the secondcomponent of the cement product described herein and mixing the twocomponents to thereby form cement. Optionally, the method can furtherinclude combining the bioactive component of the cement productdescribed herein.

As described above for the cement product, the method of forming cementdisclosed herein includes preferred embodiments of the first component,second component and optional bioactive component. Preferred embodimentsof the first component for use in the method include an epoxy resin,while more preferred embodiments of the first component include both anepoxide and a glycidyl ether group as shown in Formula 1. Even morepreferred embodiments of the first component include GMA and bis-GMA.More preferred embodiments of the second component for use in the methodinclude PEI or a derivative thereof. In the most preferred method offorming cement, the first component includes GMA or bis-GMA orethoxylated bisphenol A di(meth)acrylate and the second componentincludes PEI, PEI doped with 0.1-5% by weight of camphorquinone, or aderivative thereof.

The invention also provides a method of treating a subject in need oftreatment for a bone defect. As used herein the term “subject” caninclude a human or another animal, e.g., a bird, a fish, or a mammalsuch as a horse, cow, dog, monkey, mouse, pig, or rat. Preferably, thesubject is a human. The method of treatment generally includes formingcement according to the method of forming cement described herein andthen delivering the cement to the defective bone in the subject as partof a procedure for repairing the bone defect. Bone defects that can betreated using the method include defects due to osteoporosis, stressfracture, traumatic fracture, compression fracture, and combinationsthereof. For example, the method of treatment described herein can beused to treat patients with a vertebral bone defect due to trauma orosteoporosis. The treatment can include using the cement productdisclosed herein to form cement that is injected to the vertebra, forexample, as part of a vertebroplasty or kyphoplasty procedure tostabilize the vertebra.

The bone cement product and methods described herein can also be used inoral or dental procedures that require the use of restorative cement.Such dental procedures can include generally includes forming cementaccording to the method of forming cement described herein and thendelivering the cement to the oral or dental area of the subject thatrequires restoration, e.g., a tooth with a lesion or cavity.

The following examples further illustrate bone cement products andmethods of forming cement according to the invention but, of course,should not be construed as in any way limiting its scope.

Example 1

The following describes the preparation of an acrylic resin-basedpaste-paste restorative cement product that includes anano-hydroxyapatite bioactive component according to the invention. Thecement product includes two parts. Part A is described in Table 2 andincludes the polymerizable resin of the first component. Part B isdescribed in Table 3 and includes the polyamine of the second component.Parts A and B were each formulated as a non-dripping paste-like shearthinning cream. The bioactive component was divided between Parts A andB.

TABLE 2 (parts by weight) Glycidyl dimethacrylate (GMA) (Sartomer SR379)58.74 Ethoxylated (15) trimethylolpropanetriacrylate 5.30 (SartomerSR9035) NanoHydroxyapatite (Angstrom Medica, Inc.) 35.96

TABLE 3 (parts by weight) Polyethyleneimine (PEI-800) (Aldrich, Cat No.:408719) 55.0 NanoHydroxyapatite (Angstrom Medica, Inc.) 45.0

According to the manufacturer, PEI-800 polyethyleneimine has a branchedpolymer density of about 1.05 g/ml and average molecular weight of 800Da. Both Part A and Part B had fast and excellent dispersion, they werehighly formable, shapeable and easily delivered by a syringe deliverysystem. A cement product with a 4 to 1 ratio (by weight) of Part A toPart B was mixed on a watch glass pre-cooled to refrigerator temperature(0-5° C.). The cement mix was used to fill a ¼″ i.d. hollow tubule to aheight of 4 inches within 10 minutes. The filled tubule was placed intoa 37° C. incubator. The cement mix was dried to touch after 5 to 10minutes in the oven. The mix had no observable exotherm as determined bya thermocouple per ASTM F451-99.

The formed cement was released from the molding tubule and kept in theincubator oven for 3 days. The cement was compression tested with a MTI10K compression tester (Measurements Technology, Inc., Roswell, Ga.)using a crosshead displacement rate of 1 mm/min. The specimen was testedaccording to ASTM C773 (ASTM International (West Conshohocken, Pa.))(Procedure B) using test population 4 and compression modulus average82.25 MPa. Maximum force average was 820 N, while the average peakstress was 21.32 MPa, and average strain 28.31%.

The foregoing example demonstrates that the cement product of theinvention can be used in a method of forming cement that is injectableand has no observable rise in temperature.

Example 2

The following describes the preparation of another acrylic resin-basedpaste-paste restorative cement product with a bioactive componentaccording to the invention. The bioactive component includes bothnano-hydroxyapatite and nano-hydroxyapatite whiskers ranging in sizefrom 5-10 nm in diameter to 250 nm in length. The cement productincludes two parts. Part A is described in Table 4 and includes thepolymerizable resin of the first component. Part B is described in Table5 and includes the polyamine of the second component. Parts A and B wereeach formulated as a non-dripping paste-like shear thinning cream. Thebioactive component was divided between Parts A and B.

TABLE 4 (parts by weight) Glycidyl dimethacrylate (GMA) (Sartomer SR379)69.10 Ethoxylated (15) trimethylolpropanetriacrylate 3.78 (SartomerSR9035) NanoHydroxyapatite whiskers (Angstrom Medica, Inc.) 12.40NanoHydroxyapatite (Angstrom Medica, Inc.) 14.72

TABLE 5 (parts by weight) PEI-800 Polyethyleneimine, Aldrich, Cat No.:408719) 55.0 NanoHydroxyapatite (Angstrom Medica, Inc.) 45.0

Both Parts A and Part B had fast and excellent dispersion, were highlyformable, shapeable, and easily delivered by a syringe delivery system.A cement product with a 5.3 to 1 ratio (by weight) of Part A to Part Bwas mixed on a watch glass pre-cooled to refrigerator temperature (0-5°C.). The cement mix was used to fill a ¼″ i.d. hollow tubule to a heightof 4 inches within 10 minutes. The filled tubule was placed into a 37°C. incubator. The cement mix was dried to touch within 15 minutes in theoven. The mix had no observable exotherm as determined by a thermocoupleper ASTM F451-99.

The formed cement was released from the molding tubule and kept in theincubator oven for 3 days. The cement was compression tested with a MTI10K compression tester (Measurements Technology, Inc., Roswell, Ga.)using a crosshead displacement rate of 1 mm/min. The specimen was testedaccording to ASTM C773 (ASTM International) (Procedure B) using testpopulation 3 and compression modulus average 29.45 MPa. Maximum forceaverage was 284 N, while the average peak stress was 7.38 MPa, andaverage strain was 30.14%.

The foregoing example demonstrates another embodiment of the cementproduct of the invention that can be used in a method of forming cementthat is injectable and has no observable rise in temperature.

Example 3

The following describes the preparation of an acrylic resin-basedpaste-paste restorative cement product with a bioactive component thatincludes nano-hydroxyapatite whiskers ranging in size from 5-10 nm indiameter to 250 nm in length. The cement product includes two parts.Part A is described in Table 6 and includes the polymerizable resin ofthe first component. Part B is described in Table 7 and includes thepolyamine of the second component. Parts A and B were each formulated asa non-dripping paste-like shear thinning cream. The bioactive componentwas divided between Parts A and B.

TABLE 6 (parts by weight) Glycidyl dimethacrylate (GMA) (Sartomer SR379)70.0 NanoHydroxyapatite whiskers (Angstrom Medica, Inc.) 30.0

TABLE 7 (parts by weight) PEI-800 Polyethyleneimine, Aldrich, Cat No.:408719) 52.37 NanoHydroxyapatite whiskers (Angstrom Medica, Inc.) 47.63

Both Parts A and Part B had fast and excellent dispersion, were highlyformable, shapeable, and easily delivered by a syringe delivery system.A cement product with a 4 to 3 ratio (by weight) of Part A to Part B wasmixed on a watch glass pre-cooled to refrigerator temperature (0-5° C.).The cement mix was used to fill a ¼″ i.d. hollow tubule to a height of1.25 inches within 15 minutes. The filled tubule was placed in a 37° C.incubator. The cement mix was dried to touch within 15 minutes in theoven. The mix had no observable exotherm as determined by a thermocoupleper ASTM F451-99.

The formed cement was released from the molding tubule and kept in theincubator oven for 2 days. The cement was compression tested with a MTI10K compression tester (Measurements Technology, Inc., Roswell, Ga.)using a crosshead displacement rate of 1 mm/min. The specimen was testedaccording to ASTM C773 (ASTM International) (Procedure B) using testpopulation 1 and compression modulus average 47.4 MPa. Maximum forceaverage was 626.8 N, while the average peak stress was 16.3 MPa, andaverage strain was 47.2%.

The foregoing example demonstrates another embodiment of the cementproduct of the invention that can be used in a method of forming cementthat is injectable and has no observable rise in temperature.

Example 4

18.9631 grams of ethoxylated trimethylolpropanetriacrylate (SR9035,Sartomer) was added to 1.0380 grams of glycidyl methacrylate (SR379,Sartomer) to make the first component of the cement product. The firstcomponent was vortexed and mixed into a single phase. The secondcomponent of 0.3974 grams of PEI-800 (Aldrich, cat. no. 408719) wasmixed with 2.7643 grams of the first component on a watch glasspre-cooled to 0-5° C. The mix was stirred at ambient temperature. Theviscose fluid was transferred to a ¼″ i.d. latex tubule with capped ends(3″ long). The tubule was placed in a 37° C. incubator oven. The cementdried to touch within 15 minutes. The cement rod was released after 5days and the released rod was in the incubator oven for an additional 7days. The cement was compression tested with a MTI 10K compressiontester (Measurements Technology, Inc., Roswell, Ga.) using a crossheaddisplacement rate of 1 mm/min. The specimen was tested according to ASTMC773 (ASTM International) (Procedure B) using test population 1 andcompression modulus average 13.56 MPa. Maximum force average was 58.82N, while the average peak stress was 2.08 MPa, and average strain was16%.

The foregoing example demonstrates another embodiment of the cementproduct of the invention can be used in a method of forming cement thatis injectable.

Example 5

A two component cement product was mixed to form cement. The firstcomponent comprising 0.7143 grams of glycidyl methacrylate (SR379,Sartomer) was added to the second component comprising 0.4713 grams ofPEI-800 (Aldrich, cat. no. 408719). A white viscose fluid formedimmediately with no temperature raise. The fluid was stirred well atambient temperature and transferred to a ¼″ i.d. latex tubule withcapped ends (3″ long). The tubule was placed in a 37° C. incubator oven.The cement dried to touch within 15 minutes. The cement rod was releasedafter 5 days and the released rod was in the incubator oven for anadditional 7 days. The cement rod was compression tested with a MTI 10Kcompression tester (Measurements Technology, Inc., Roswell, Ga.) using acrosshead displacement rate of 1 mm/min. The specimen was testedaccording to ASTM C773 (ASTM International) (Procedure B) using testpopulation 1 and compression modulus average 13.56 MPa. Maximum forceaverage was 58.82 N, while the average peak stress was 2.08 MPa, andaverage strain was 16%.

The foregoing example demonstrates another embodiment of the cementproduct of the invention that can be used in a method of forming cementthat is injectable.

Example 6

This example compares the exothermic profile of various embodiments ofthe cement product according to the invention, each embodiment havingdifferent relative amounts of the first and second component.

The relative amounts of the first component, comprising GMA, and thesecond component, comprising PEI, were varied as indicated in Table 8.Table 8 also indicates (a) predicted millimoles of double bonds (C═C) inthe glycidyl groups of the GMA (assuming 100% purity and GMA monomericmolecular weight of 142.15 daltons), (b) millimoles of PEI repeat units(assuming 100% purity and repeat unit molecular weight of 43.07daltons), (c) equivalent ratio of GMA glycidyl groups to PEI repeatunits, (d) the observed temperature rise after mixing for two minutes,and (e) setting time in a 37° C. incubator oven after N₂ gas purging.

TABLE 8 Cement Product 6-A 6-B 6-C 6-D 6-E 6-F GMA 0.7169 1.4287 1.12220.6841 0.6425 0.7361 (grams) Glycidyl 5 10.05 7.89 4.8 4.5 5.17 (C═C)mmole PEI 0.4387 0.6770 0.4307 0.5444 0.6066 0.7356 (grains) PEI 10.1815.7 10.00 12.64 14.08 17.08 mmole GMA:PEI 0.49:1 0.64:1 0.79:1 0.38:10.32:1 0.30:1 mmole ratio Tempera- 27-29 27-29 27-28 27-29 25-28 25-28ture rise (° C.) Set time 35 135 135 35 38 35 (min.)

The results in Table 8 indicate that when GMA is in excess, the polymersystem is more sluggish in curing. On the other hand, when thestoichiometric ratio of reacting functional groups are equal, or whenPEI is in excess, more rapid curing is achieved.

A clear tubule shaped sample of formed cement product 6-A (0.49:1 moleratio of GMA:PEI) showed maximum compression strain of 81.2%, peakstress of 48.5 MPa, and compression module of 154.84 MPa. Upon releaseof the strain, the sample returned to its original length within a fewseconds. However, this aliphatic neat polymer system is not hydrolysisresistant.

The results are consistent with the following polymerization model. WhenPEI equivalents are in excess, Michael addition reactions (of C═C doublebonds and the primary and secondary amine groups in the PEI) aredominant and there is less dampening of exothermic temperature rise,since there are not enough endothermic reactions available to compensatefor the exothermic glycidyl-amine reaction. When excess PEI is reducedand there are nearly equal amounts of PEI repeat equivalents as C═Cdouble bond equivalents, or when there is a slight molar excess of C═Cdouble bond groups (e.g., a slight excess of GMA) the system can beginto favor the endothermic reactions that dampen the exothermictemperature rise. This model suggests that adding a vinyl or allylcomponent in addition to the first GMA component can supply additionaldouble bonds, which are used not only for Michael addition to amines onPEI but also for carbocation reaction sites. In other words, vinyloligomers such as (bis-GMA) or other vinyl oligomers described hereinmay be added as an additional polymerizable resin to the first andsecond components of the cement product. It should be noted, however,that too much excess GMA can result in a slower set time.

Example 7

The following describes the preparation of another acrylic resin-basedpaste-paste restorative cement product with a bioactive componentaccording to the invention. The bioactive component includes SpectrumChemicals poorly crystallized calcium phosphate tribasic (Catalog#C1155) dense powder. The cement product includes two parts. Part A isdescribed in Table 9 and includes the polymerizable resin of the firstcomponent. Part B is described in Table 10 and includes the polyamine ofthe second component. Parts A and B were each formulated as anon-dripping paste-like thick ointment. The bioactive component wasdivided between Parts A and B.

TABLE 9 (parts by weight) Ethoxylated(2) Bisphenol A Diacrylate (SPPM-193) 58.48 Calcium Phosphate Tribasic (Spectrum Chemical C1155) 41.52

TABLE 10 (parts by weight) PEI-800 Polyethyleneimine, Aldrich, Cat No.:408719) 42.44 Calcium Phosphate Tribasic (Spectrum Chemical C1155) 57.56

Both Parts A and Part B were thick ointment-like pastes. A cementproduct with a 2.1 to 1 ratio (by weight) of Part A to Part B was mixedon a watch glass. The cement mix was used to fill a ¼″ i.d. hollowtubule to a height of 6 inches within 3 minutes. The cement mix wasdried to touch within 3 minutes at room temperature. The mix hadexotherm temperature raise of 6° C./min as determined by thermocoupleper ASTM F451-99.

The formed cement was released from the molding tubule and kept at roomtemperature for 16 days. The cement was compression tested with a MTI10K compression tester (Measurements Technology, Inc., Roswell, Ga.)using a crosshead displacement rate of 10 mm/min. The specimen wastested according to ASTM C773 (ASTM International) (Procedure B) usingtest population 3 and compression modulus average 176 MPa. Maximum forceaverage was 1357 N, while the average peak stress was 40.8 MPa andaverage strain was 30.72%.

Example 8

The following describes the preparation of another acrylic resin-basedpaste-paste restorative cement product without a bioactive componentaccording to the invention. The neat polymeric resin product includespart A and part B as described in Table 11. Parts A and B were eachformulated as a liquid resin.

TABLE 11 (parts by weight) A: Ethoxylated(2) Bisphenol A Diacrylate (SPPM-193) 82.9 B: PEI-800 Polyethyleneimine, Aldrich, Cat No.: 408719) 17.1

Both Parts A and Part B were free flowing low viscosity liquid. Athermoset product with a 4.85 to 1 ratio (by weight) and 1 to 1 by moleof Part A to Part B was mixed on a watch glass. The cement mix was usedto fill a ¼″ i.d. hollow tubule to a height of 6 inches within 5minutes. The cement mix was dried to touch within 15 minutes in anincubator oven. The mix had little exotherm temperature rise asdetermined by thermocouple per ASTM F451-99.

The formed thermoset solid tube was released from the molding tubule andkept in the incubator oven for 14 days. The thermoset was compressiontested with a MTI 10K compression tester (Measurements Technology, Inc.,Roswell, Ga.) using a crosshead displacement rate of 10 mm/min. Thespecimen was tested according to ASTM C773 (ASTM International)(Procedure B) using test population 5 and compression modulus average 30MPa. Maximum force average was 2376 N, while the average peak stress was75 MPa and average strain was 50.28%. The solid tube is compressible andrecovered to its original length after the stress was released.

Example 9

The following describes the preparation of another acrylic resin-basedpaste-paste restorative cement product without a bioactive componentaccording to the invention. The neat polymeric resin product includespart A and part B as described in Table 12. Parts A and B were eachformulated as a liquid resin.

TABLE 12 (parts by weight) A: Ethoxylated(2) Bisphenol A Diacrylate (SPPM-193) 75.85 B: PEI-800 Polyethyleneimine, Aldrich, Cat No.: 408719)24.15

Both Parts A and Part B were free flowing low viscosity liquid. Athermoset product with a 3 to 1 ratio (by weight) and 1 to 1.6 by moleof Part A to Part B was mixed on a watch glass. The cement mix was usedto fill a ¼″ i.d. hollow tubule to a height of 6 inches within 8minutes. The cement mix was dried to touch within 25 minutes in anincubator oven. The mix had little exotherm temperature rise asdetermined by a thermocouple per ASTM F451-99.

The formed thermoset solid tube was released from the molding tubule andkept in the incubator oven for 14 days. The thermoset was compressiontested with a MTI 10K compression tester (Measurements Technology, Inc.,Roswell, Ga.) using a crosshead displacement rate of 10 mm/min. Thespecimen was tested according to ASTM C773 (ASTM International)(Procedure B) using test population 5 and compression modulus average76.53 MPa. Maximum force average was 650 N, while the average peakstress was 20.33 MPa and average strain was 50.91%. The solid tube iscompressible and recovered to its original length after stress wasreleased.

Example 10

The following describes the preparation of another acrylic resin-basedpaste-paste restorative cement product without a bioactive componentaccording to the invention. The neat polymeric resin product includestwo parts. Part A and part B are described in Table 13. Parts A and Bwere each formulated as a liquid resin.

TABLE 13 (parts by weight) A: BisGMA (Sartomer CN151) 85.66 B: PEI-800Polyethyleneimine, Aldrich, Cat No.: 408719) 14.34

Parts A is a sticky high viscosity fluid and was heated to 37° C. tolower its viscosity and Part B is a free flowing low viscosity liquid. Athermoset product with a 4 to 1 ratio (by weight) and 1 to 1 by mole ofPart A to Part B was mixed on a watch glass The cement mix was used tofill a ¼″ i.d. hollow tubule to a height of 8 inches within 20 minutes.The thermoset mix was sticky and the hollow tubule was end-capped with astop-cork plug then it was placed in a 37 C incubator oven. The mix hadlittle exotherm temperature rise as determined by thermocouple per ASTMF451-99.

It was left to harden overnight. The formed thermoset solid tube waskept in the incubator oven for 10 days. Then the hollow tubule wasremoved. The thermoset was compression tested with a MTI 10K compressiontester (Measurements Technology, Inc., Roswell, Ga.) using a crossheaddisplacement rate of 10 mm/min. The specimen was tested according toASTM C773 (ASTM International) (Procedure B) using test population 4 andmaximum compression modulus was 434 MPa. Maximum force was 4287 N, whilethe maximum peak stress was 111 MPa, and maximum strain was 70%. Thesolid tube is compressible and recovered to its original length afterstress was released.

The foregoing example demonstrates that the cement product of theinvention can be used in a method of forming cement that is injectableand is only mildly exothermic. The foregoing example also indicates thatthe ratio of first and second components in the cement product of theinvention can be adjusted to further reduce the exothermic rise intemperature produced by mixing the components of the cement product.

Example 11

The following describes experiments performed to determine thetemperature rise and set times that result from varying the type and/oramount of a first or second component in a cement product of theinvention.

In a first set of three experiments, SR9035 was mixed with one of thefollowing four grades of PEI linear PEI with average molecular weight of423 daltons (PEI-423), branched PEI with average molecular weight of 800daltons (PEI-800). PEI with average molecular weight of 1800 daltons(PEI-1800), or PEI with average molecular weight of 10,000 daltons (PEI10,000). Individual mixtures included a mole ratio of 0.8:1, 1:1, or1.2:1 of SR9035 to each grade of PEI. The results depicted in FIGS. 1, 2and 3 show a similar temperature rise for each mixture. Maximumtemperature rises were all well below body temperatures.

PEI-10000 did not set overnight any of the three tested ratios, whilePEI-1800 set only at the excess ratio of 1.2:1 overnight. PEI-800 andPEI-423 set within 5 to 15 minutes and hardened 30 minutes after mixingfor all 3 mole ratios.

The foregoing example demonstrates a stoichiometry tolerance of at least+/−20% for achieving reasonably quick set and hardening times forcements including PEI-800 and PEI 423. The results also indicates thatthe concentration of primary amine in PEI's is a determining factor ofthe set time, since PEI-10,000 and PEI-1800 have a much lowerconcentration of primary amine (chain-ends) than PEI-800 or PEI-423.

Example 12

The following describes experiments performed to determine thetemperature rise and set times that result from varying the type and/oramount of a first or second component in a cement product of theinvention.

Experiments were performed under a cold visible 13 watt OTT-LITE lamp.Mixed reaction components were formed into a dough at room temperatureand then placed in an incubator oven at 37.5+/−1° C. Reactions stoppedwhen the dough hardened. In each reaction the second component wasPEI-800. PEI-800 was reacted with (a) non-alkoxylated pentaerythritoltriacrylate (PETA) at a PEI to triacrylate mole ratio of 0.6:1, 0.8:1,1:1 or 1.2:1, (b) propoxylated (3) trimethylolpropane triacrylate(TMPTA) at a PEI to triacrylate mole ratio of 0.6:1, 0.8:1, 1:1 or1.2:1, or (c) propoxylated (5) glycerol ethoxylatedbisphenol-A-triacrylate at a PEI to triacrylate mole ratio of 1:1 or1.2:1. Exotherm temperature rises over time are shown in FIGS. 4, 5, and6.

PEI-800 to non-alkoxylated PETA mole ratios of 1.2:1 and 1:1 generatedrapid temperature rises up to 50° C. The PETA reaction set and was veryhard within 2 minutes, making it the fastest of the triacrylates with acommendable temperature rise.

Results shown in FIGS. 4, 5, and 6 of the foregoing example indicatesthat when PEI is stoichiometric or slightly in excess, the triacrylatesset faster and, when PEI is deficient, the set reactions are moresluggish. Results shown in FIGS. 4, 5, and 6 also indicate that the moreextensively alkoxylated the triacrylates, the slower the set time andthe lower the temperature rise. Thus, degree of alkoxylation affects settime as well as exotherm temperature rises. Additionally, the exampleindicates that propylene glycol moieties in the oligomer can act as (i)a solvent that dilutes PETA and (ii) a heat sink to help lower theexotherm heat.

Example 13

The following example describes experiments performed to determine thetemperature rise and set times associated with cement products of theinvention formed by mixing various ratios of a first component and asecond component that further includes a low dose of 222 ppmcamphorquinone (CQ) photoinitiator.

Reaction conditions were the same as those described for Example 12,except that 222 ppm of CQ photoinitiator was dissolved into PEI-800.CQ-doped PEI-800 was reacted with (a) PETA at a PEI to triacrylate moleratio of 0.6:1, 0.8:1, 1:1 or 1.2:1, (b) propoxylated (3) TMPTA at a PEIto triacrylate mole ratio of 0.6:1, 0.8:1, 1:1 or 1.2:1, or (c)propoxylated (5) glycerol ethoxylated bisphenol-A-triacrylate at a PEIto triacrylate ratios of 1:1. Results are shown in FIGS. 7, 8, and 9.

The results depicted in FIGS. 7, 8, and 9 of the foregoing exampleindicate that (i) when PEI is in slight excess, the triacrylates setfaster, (ii) when PEI is deficient, set reactions are more sluggish(iii) increased alkoxylation of triacrylates slows down set time andlowers exotherm temperature, and (iv) propylene glycol moieties in theoligomers can act as (a) a solvent that dilutes PETA and (b) a heat sinkto help lower the exotherm heat. Again, PETA by far is clearly thefastest setting of the triacrylates and exhibits a commendabletemperature rise. The foregoing example also indicates that the low doseof CQ photoinitiator has little or no effect at 0.6:1 PEI:triacrylateratios, which suggests that excess triacrylates engaged in little or nofree radical polymerization. However, the results depicted in FIG. 7indicate that low dose CQ photoinitiator did produce a faster initialtemperature rise in the 0.8:1 mole ratio PEI/PETA system, such that the0.8:1 mole ratio system eventually matches the temperature rise of the1:1 system.

Example 14

The following example describes experiments performed to determine thetemperature rise and set times associated with cement products of theinvention formed by mixing various ratios of a first component and asecond component that further includes 0.5% CQ photoinitiator.

Reaction conditions were the same as those described for Example 13,except that CQ photoinitiator was dissolved in PEI-800 to 0.5% byweight. CQ-doped PEI-800 was mixed with (a) PETA, (b) propoxylated (3)TMPTA, (c) propoxylated (5) glycerol ethoxylatedbisphenol-A-triacrylate, or propoxylated (6) TMPTA. Each mixtureincluded a PEI to triacrylate mole ratio of 0.6:1, 0.8:1, 1:1 or 1.2:1.Results are shown in FIGS. 10, 11, 12, 13

The results shown in FIGS. 10, 11, 12, and 13 of the example indicatethat (i) when PEI is in slight excess, the triacrylates set faster, (ii)when PEI is deficient, set reactions are more sluggish (iii) increasedalkoxylation of triacrylates slows down set time and lowers exothermtemperature, and (iv) PETA is clearly the fastest setting of thetriacrylates and exhibits a commendable temperature rise.

As depicted in FIG. 10, the 0.5% CQ photoinitiator does produce a fasterinitial temperature rise in the 0.8:1 mole ratio PEI/PETA system, whicheventually surpasses that seen in the 1:1 mole ratio PEI/PETA systemshown in FIG. 10. This result may indicate that Michael additionreactions compete with visible light initiated free polymerizationreactions due to a PEI deficiency in the 0.8:1 mole ratio PEI/PETAsystem.

The foregoing example indicates that stoichiometry of PEI andtriacrylates can be important to achieving the optimum cure for a givenapplication. The example indicates that the PEI mole ratios have avariability tolerance of up to +/−20%.

Example 15

The following example describes experiments performed to determine thetemperature rise and set times associated with cement products of theinvention formed by mixing various ratios of a first component and asecond component with or without CQ photoinitiator.

Reaction conditions were the same as those described for Examples 12, 13and 14, except as indicated. In the first set of experiments PEI-800 wasmixed with ethoxylated (2) Bisphenol A diacrylate (E(2)BisDA)(ethoxy:phenol ratio of 1:1) or ethoxylated (4) bisphenol A diacrylateE(4)BisDA (ethoxy:phenol ratio of 2:1). In the second set ofexperiments, 222 ppm CQ photoinitiator was dissolved in PEI-800, and thedoped PEI-800 was mixed with E(2)BisDA or E(4)BisDA. In the third set ofexperiments, 0.5% by weight CQ photoinitiator was dissolved in PEI-800,and the doped PEI-800 was mixed with E(2)BisDA or E(4)BisDA. Eachindividual mixtures included a (doped or undoped) PEI-800:diacrylateratio of 0.6:1, 0.8:1, 1:1 or 1.2:1. Temperature rises over time areshown in FIGS. 14, 15, 16, 17, 18, and 19.

The maximum temperature rise for all reactions was below bodytemperature. For both sets of reactions, (i) the set times for aE(4)BisDA system is double that of the respective E(2)BisDA system and(ii) at PEI-800:diacrylate ratios of 0.8:1, 1:1 or 1.2:1, a E(4)BisDAsystem are more rubbery than the respective E(2)BisDA system. Generally,a higher PEI-800 ratio and a longer time in incubator oven gave a harderfinish.

The CQ photoinitiator had little or no effect at PEI-800:diacrylateratios of 1:1 and 1.2:1 for both diacrylates. However, increasing dosesof CQ photoinitiator caused earlier and faster temperature rises forsystems with lower PEI-800:E(2)BisDA ratios of 0.6:1 and 0.8:1, relativeto the higher 1:1 and 1.2:1 ratios. The effect was less pronounced forE(4)BisDA systems.

A short light treatment (prior to oven incubation) of the dough formedusing 0.6:1 PEI-800:E(2)BisDA systems with CQ photoinitiator, shortenedset time and improved finish after oven incubation overnight. The 0.6:1PEI-800:E(2)BisDA system with 0.5% CQ photoinitiator produced a rockyhard finish after incubation overnight.

The foregoing example indicates that, when PEI is stoichiometric (1:1)or in excess (1.2:1), Michael additions are preferred and, therefore,temperature rises are minimized. The example also indicates that higherethoxylation results in slower Michael addition reactions, which reducesthe impact of impact of photoinitiator CQ on the free radicalpolymerization of E(4)BisDA.

Example 16

The following example describes the temperature rise and set timesassociated with cement products of the invention formed by mixingPEI-800 with various relative amounts of a first component that includesequimolar mixture of E(2)BisGMA, BisGMA, and GMA.

Reactions conditions were the same as those described for Example 12,except where explicitly noted. Each individual mixture includedPEI:first component ratio of 0.8:1, 1:1, or 1.2:1. Results are shown inFIG. 20. The tested system did not set within 15 minutes.

The foregoing example indicates that in order to optimize the testedsystems to achieve a 15 minute set time, it may be necessary to use ahigher power visible light lamp and/or to adjust levels ofphotoinitiator, thermoinitiator, and Michael addition reactions.

Example 17

The following example illustrates compression strength characteristicsof several cement products of the invention.

Each first component resin was mixed with PEI-800 at the specified ratioindicated in Table 14. After setting, each product was evaluated with anMTI 10K compression tester (Measurements Technology, Inc., Roswell, Ga.)with a crosshead displacement rate of 10 mm/min. Compression testing wasperformed according to ASTM C773 (ASTM International) (Procedure B).Work and set times as well as strength characteristics for each productare shown in Table 14.

TABLE 14 Work PEI-800: Average Average First time/ First CompressionCompression Component Set time Component Modulus strength Average Resinmin.) Mole ratio (MPa) (MPa) Deflection % E(2)BisDA  5 min/   1:1 30 7550.28% 15 min E(2)BisDA  8 min/ 1.6:1 76.53 20.33 50.91% 25 min BisGMA20 min/   1:1 434 111   70% GMA (1:1 20 hrs mole ratio) SR9035  5 min/  1:1 13.56 2.08   16% GMA (1:1 15 min mole ratio) GMA 30 min/   1:1154.84 48.5 81.82%  5 days

The BisGMA-GMA-PE system had a maximum compression modulus of 434 MPa, amaximum force of 4287 N, maximum peak stress of 111 MPa, and maximumstrain of 70%. The solid tube was compressible and recovered to itsoriginal length after stress was released. The BisGMA-GMA-PEI system hasbetter hydrolysis resistance.

To control the hydrophilicity of finished polymer systems,divinylbenzene (DVB) and vinyl benzyl chloride (VBC) were mixed withPEI. DVB highly inhibited Michael addition, and therefore may requireadding a Michael addition catalyst in these systems. The PEI/VBC systemunderwent Michael addition similarly to PEI/diacrylate systems. If PEIwas deficient, prolonged heating at 37° C. overnight, resulted in thePEI/VBC giving off HCl and foaming of the neat polymer cement. Thus, aslight excess of PEI in the cement formulation is required to neutralizethe excess HCl.

The preceding example shows that BisGMA-GMA-PEI has good work time(15-30 minutes) and excellent compression strength characteristics foruse in bone cement formulation. To lower the viscosity of BisGMA, e.g.,for use in a filled cement, a relatively small amount of GMA orethoxylated (2) bisphenol A diacrylate can be added.

Additionally, the example shows that the E(2)BisDA-PEI (1:1 ratio)system has fast (5-10 minutes) dough (work), good optimum hardness ofgreater than 70 MPa and high deflection % of greater than 50%. Thesecharacteristics indicate that both BisGMA-GMA-PEI and E(2)BisDA-PEI (1:1ratio), or derivatives thereof may be used in synthetic cartilagecompositions.

Example 18

The following example illustrates the compression strengthcharacteristics of several cement products of the invention that includea powder filler.

Fillers used in this example had the following characteristics: densepowder particle size: <50 micron, dense power surface area: 0.5 to 5m2/gm, dense powder pore volume: <0.01 cm3/gm. Specific fillers includedSP2525, a 200 mesh glass powder from Specialty Glass Inc. (Oldsmar,Fla.), BAB-HA-G1, BAB-LHA-G2, and BAB-HA TCP-G2 dense powders fromBerkeley Advanced Biosystem (Berkeley, Calif.), C1155, tribasic calciumphosphate powder from Spectrum Chemical (Gardena, Ca), Dense HA, a densepowder from chipped compressed and fired slogs from Angstrom Medica,Inc. (AMI, Woburn, Mass.) SD1K HA, a spray dried and calcined (at 1000°C.) powder from AMI, and nanoHAW whiskers from AMI.

A first component, PEI-800 (with or without CQ photoinitiator) and afiller component were mixed according to relative amounts indicated inTable 15. Work and set times as well as strength characteristics foreach mixture are shown in Table 15.

TABLE 15 Average First Work/ Average Compression Component CurativeFiller Set T C Modulus strength Average Resin (R) (C) Filler w/w %(min.) (MPa) (MPa) deflection % SR9035 PEI-800 AMI 33% 5 min/ 77.5 21.3335.4% GMA nanoHA 10 min DVB-80 SR9035 PEI-800 nano-HA 33% 12 min/ 38.512.5 37.4% BisGMA 25 min GMA VBC E2BisDA PEI-800 AMI's 35% 5 min/ 136.339.6 34.6% CQ nHAW 15 min E2BisDA PEI-800 AMI's 45% 5 min/ 101 21 21.8%CQ nHAW 15 min E2BisDA PEI:800 SD1K 50% 9 min/ 582 59.7 31.7% BisGMA HA39 min GMA E2BisDA PEI:800 SD1K 50% 15 min/ 255 52 25.8% HA 60 min GMAPEI-800 AMI 63% 15 min/ 171.3 48.2 34.6% SR9035 Dense + 25 min DVB-80nanoHA BisGMA PEI:800 SD1K 67% 15 min/ 117 22.3* 23.6% GMA HA 60 min GMAPEI-800 BAB- 70% 13 min/ 633.0 84 15.7% DVB-80 HA-G1 26 min SR9035SR9035 PEI-800 SGI 74% 10 min/ 47 21.5* 50.3% BisGMA Glass 18 min GMAPowder VBC GMA PEI-800 BAB- 78% 10 min/ 86.5 6.5% 11.6% DVB-80 HA-G1 20min SR9035 & G2 GMA PEI-800 BAB-HA 78% 10 min/ 294 32 14.6% DVB-80TCP-G2 20 min SR9035

Additional experiments indicated that NanOss nanocrystalline HA powdercould not suitable be loaded into PEI-800 cement systems beyond 50%(w/w), while for acrylate systems, loading was limited to less than 40%(w/w). These limits are related to the high microporosity of thenanocrystalline powder (surface areas are in the range of 400 m²/gm andaverage particle size is in the range of 6 microns). The powder may havesoaked a significant amount of monomer liquid in the pores, thussequestering and reducing the availability of reactive oligomers forcuring as well as producing localized improper stoichiometry reactionswhich resulted in brittle products.

Generally when using PEI as a curative, viscosity can be diluted withGMA resin, either alone or with another waxy oligomers such as BisGMA.However, GMA tends to generate tremendous exotherm heat when epoxy-epoxyhomo-polymerization and epoxy-amine chain reactions occur. Therefore,the amount of GMA used in the formulation should be limited.

Mixtures including (a) predominately aliphatic (GMA) and hydroscopic(SR9035 and PEI) backbones and (b) tricalcium phosphate filler faileddissolution tests within hours if not minutes. Mixtures containingaromatic and hydroscopic (BisGMA, E(2)BisDA, DVB, VBC) were more stablein dissolution tests. However. DVB and VBC have a distinct smell, whichrenders them less desirable for some applications. Using SR9035 aspredominated resin can also be unfavorable because it quickly decomposesand dissolves by de-Michael addition.

FIG. 21 shows compression strength of two cements more than 24 hoursafter set, at body temperatures. The first cement included aE(2)BisDA:PEI (4:1) and the second cement included E(2)BisGA+BisGMA:PEI(4:1), while both cements also included a 50% (w/w) loading of SD1K HA(spray dried and 1000° C. calcined HA dense powder). TheE(2)BisGA+BisGMA:PEI (4:1) dense powder system achieved a targetedcompression strength of 50 MPa after one day at body temperature.

FIG. 22 shows compression strength as a function of curing time for acement including E(2)BisDA+BisGA:PEI-423 and 33.7% w/w loading of AMITCP (IBC-8) powder. Compression strength was measured at 37° C., in thepresence or absence of simulated body fluid (SBF). Both the control andthe SBF-treated cement achieved and maintained a targeted compressionstrength of greater than 50 MPa during the 48 hours testing period.

This example indicates that compression strengths of ˜50-84 MPa wereassociated with dense particle hydroxyapatite fillers, loaded at 50% to70% by weight. Good results were also seen with 33.7% by weight loadingof TCP (IBC-8) powder. Outside of this loading range, compressionstrength suffered (either due to intrinsically weak nanoHA whiskers ornanoHA powders or due to insufficient dispersion and wetting). Airbubble entrapment likely contributed to weak compression strength ofcertain highly loaded formulations. Longer machine pigment grinding ofhigher than 70% powder loading may reduce defects of the finishedcomposites. Additionally surface modified functional powders havingcompatible reactive functionality with the first and second componentwill likely improve mechanical strength of the finished cement.

Example 19

The following example illustrates the compression strengthcharacteristics of cement products of the invention formed withcomponents that model a liquid aromatic diamine.

A first component included a mixture a BisGA and ethoxylated (2)bisphenol A diacrylatephenylenediamine (mPDA). The second componentincluded (a) 30% m-phenylenediamine (mPDA), (b) 30% o-cyclohexanediamine(o-CHDA), and (c) 40% PEI-800 in a weight ratio of 5:3:1 or 5:3:2,respectively. By way of background, mPDA is a low melting point solidthat can be dissolved in liquid polyethyleneimine, ando-cyclohexanediamine is a liquid cyclic-aliphatic diamine. The first andsecond components were reacted in 1:1 mixture and set polymer was placedin air (control) or in 1× simulated bodily fluid (SBF) at 37° C. FIG. 23shows the compressive strength as a function of cure time of the neatpolymer formed from the 5-3-1 second component. FIG. 24 shows thecompressive strength as a function of cure time of the neat polymerformed from the 5-3-2 second component.

The 5-3-1 polymer was so hydrophobic that water beaded up on itssurface. Moreover after soaking in 1×SBF for 3 weeks, the 5-3-1 polymersample's diameter increased about 6%. The reduced compression strengthof the 5-3-2 polymer in SBF may be due to excess hydrophilic PEI-800branches, which absorb water and plasticize the polymer.

This example shows that a nucleophile curative system containingm-phenylenediamine polyethyleneimine and o-deyclohexane-diamine(o-CHDA), if set with aromatic containing enone oligomers such as BisGAcan have a very high compression strength of above 50 MPa. Moreover,such a system preserves its excellent dimensional and hydrolyticstabilities in SBF at body temperatures.

Example 20

The following example illustrates the compression strengthcharacteristics of cement products of the invention that include (i)amino acids with amino-groups in their side chains or (ii) a heterocylicaromatic diamine.

The side chain amino groups of certain amino acid can serve asnucleophiles for the Michael addition to enones. Generally, amino acidsare flaky or crystalline solids at room temperature, thus, they shouldbe dissolved in a liquid to effectively participate in the set reaction.In the following experiments L-phenylalanine (PHE), L-Tryptophan (TRP),L-Lysine (LYS), L-cysteine (CYS), L-tyrosine (TYR), L-arginine (ARG),L-histidine (HIS) were dissolved in PEI and/or 1,4-diaminobutane (DAB).Certain amino acid solutions had a distinctive smell. DAB has a meltingpoint of 25° C., although, upon moderate heating, amino acids and DABformed a low viscosity liquid and stay as a liquid at room temperatures.This indicates that DAB containing systems may be useful for forming insitu biological active oligo-peptide putty systems for applicationswhere quick resorbability is desired.

Heterocyclic aromatic diamine containing compounds, which are similar topurine and pyrimidine containing biological nucleotides, were alsodissolved in DAB and PEI. Dissolved compounds included guanidinecarbonate (GUAC), diaminopurine (DAP), diaminopurine hemisulfate(DAPHS), 2,4-diamino-6-hydroxypyrimidine (DAHP), and 2-mecapto-uracil(DAHMP).

The solubility (w/w) of some of above mentioned materials in PEI wereGUAC—25.2%, DAP—18.8%, DAHP—13.8%, PHE—61.24%, TRP—46.46%, ARG—21.9%,and CYS—18.2%. The solubility (w/w) of above mentioned materials in DABwere PHE—28%, TRP—29.4%, CYS—19.5%, LYS—16.1%, and TYR—32.1%.

A fast dough prototype containing CYS was developed, which has a polymercomposition of A:B of 6.674:1, wherein Part A includes E(2)BisDA+BisGA(1:1 mole equivalents), and Part B includes Cysteine (18.23% w/w)dissolved in PEI-800.

Monomers were compounded by hand in a 250 mL PP vessel. After vigorousand thorough mixing, resin was poured and kneaded into SS-compressionspecimen mold. The mold compression plates were clamped shut usingC-clamp and placed in oven for 24 hours at 37° C. to fully set.Specimens were then ejected from the mold and arbitrarily split into twosubgroups. One group was placed into SBF at 37° C. while the other wasplaced in a weigh boat exposed to air and put into the same oven at 37°C. The control and SBF samples were allowed to cure for an additional 48hours before being tested.

The first compression test was taken after specimens had been exposed toSBF for 48 hours (total cure time of 72 hours). Compression modesbetween SBF and control samples were indistinguishable. Samples did notshow any swelling, weight gain, or surface erosion.

Table 16 below details the compressive strength of both control (air)and test (SBF) cured specimens. Several samples from data points 1 and 2were censored due to large air voids within the specimen.

TABLE 16 Data Cure Time Compressive % % point Type (hours) Strength(mPa) Swelling(D) Swelling(L) 0 — 0 0 — — 1 Control 72 39 0 0 1 SBF 7274.5 0.80 1.18 2 Control 168 35.8 0 0 2 SBF 168 12.2 1.26 1.42

The high strength of SBF cured samples after 72 hours is misleading.Neat polymeric samples tend to undergo drastic deformation, both inheight and cross-sectional area when loaded. The test performed does notaccount for the drastic increase in load area resulting in reportedstresses which are inaccurate and irrelevant. The goal of eachcompressive test is to determine the force required to cause a givenpart to yield. To this, the test is set to terminate when the normalforce drops by 5% between any two points. Unfortunately, often thestress/strain curve does not facilitate this termination and the stressincreases quasi-linearly until a max deflection of 55%. In short, sampleC from SBF data point one was recorded as 104 MPa, when in reality thesample yielded at much lower stress.

The samples were allowed to cure three additional days, in solution andin air, before additional compressive testing was performed. Samplescured in SBF did not show any immediate qualitative signs of waterdegradation. Surfaces were smooth and stiff, and did not yield to thecaliper faces during measurement, a quality characteristic ofplasticized samples. As illustrated by Table 16, quantitativemeasurements did not show significant swelling (1-2%). The percentagesshown in Table 16 indicate percent increase in diameter and length oftest samples compared to control samples. Test samples cured in SBFyielded under significantly smaller loads than air cured controls.Failure modes of each were nearly identical, with an increase indiameter concentrated at the load faces while the body of the slugremained unchanged. The mere lack of strength and stiffness of testsamples indicated plasticizing of the polymer by the fluid.

Example 21

The following example illustrates the characteristics of certain cementproducts of the invention.

Pentaerythritol triacrylate (PETA) reacted with o-cyclohexanediamine(o-CHDA). Putty set within 3 minutes with a maximum exotherm temperatureof 58° C. The finished specimen was hard, having a compression strengthof 25 MPa. Surprisingly, the set neat putty completely dissolved inwater within 3 days. The rapid dissolution may be related to bothingredients being aliphatic.

Other monomers known to provide high glass transition temperature (Tg)finished polymers were reacted with PEI. These monomers were mostlyaliphatic and included diethyleneglycol diacrylate, dipropyleneglycoldiacrylate, glyceryl propoxy triacrylate, pentaerythritol triacrylate,and tris (2-hydroxy ethyl) isocyanurate triacrylate. They improved thehardness and compression strength of the set putty but did not affecttheir fast dissolution. These fast dissolution systems should work wellfor controlled release of bone nutrients, e.g., in bone void fillersapplications.

We also tried to introduce simultaneous free radical polymerization andMichael addition by adding both benzyl peroxide (BPO) andp-dimethyltoluidine (pDMT) into the system. BPO and pDMT were intendedto anchor C—C linkage on the main polymer chain and secure hydrolyticalstability over time. Generally, since the reactions involved arecompeting simultaneous rapid reactions, room temperature Michaeladdition occurred first, forming C—N imine main chain and preventing theheat accumulation needed to initiate free radical C—C main chainformation.

The ratio of C—C linkage formation in the main chain can be increased,however, by using acetoacetonates containing monomers such as2-(acryloyloxy)ethyl acetoacetonate (Aldrich Cat no.: 497126) or allylacetoacetate (Aldrich cat. No.: 254959) to react with di(meth)acrylatesor tri(meth)acrylates. Michael addition occurs at higher temperaturesand does not require diamines participation. BPO and pDMT can beintroduced to accelerate the rates of reaction, thereby facilitating thesimultaneous occurrence of hybrid free radical reactions and Michaeladdition reactions.

This example shows that certain combinations of an aliphatic firstcomponent and an aliphatic second component form a hard cement thatrapidly dissolve in aqueous environments. These systems may be usefulfor applications such as bone void fillers. For weight bearing, longterm, slow dissolution applications, the cements may require usingmonomers with an aromatic and/or other hydrophobic moiety.

Example 22

The following example illustrates the exotherm characteristics ofcertain cement products of the invention.

The following epoxy-containing first components were developed: 5.7.1,which includes ARALDITE 506 epoxy resin (Ciba-Geigy, Brewster, N.Y.) andpoly[(phenyl glycidyl ether)co-formaldehyde](PPGEF) (1:1milliequivalents); 5.7.2, which includes PPGEF+Neopentyl glycoldiglycidyl ether (NPGDGE) (3:1 milliequivalents); and 5.7.3, whichincludes PPGEF+N,N-Diglycidyl-4-glycidyloxyaniline (DGGOA) (2.5:1milliequivalents). Each of these first components was compounded with astoichiometric (i.e., based on PEI-800 dalton oligomer mole equivalentweight of 43 dalton) amount of PEI-800 loaded with 15% (weight of totalpolymer) ZnS. More specifically, PEI-800 was measured first, ZnS powderwas incorporated into the PEI-800, and then the first component wasadded and mixed vigorously. Cement C090 included 4.40 g first component5.7.1, 1.057 g PEI-800 and 0.963 g ZnS. Cement C091 included 4.98 gfirst component 5.7.2, 1.133 g of PEI-800, and 1.079 g ZnS. Cement C092included 4.59 g first component 5.7.3, 1.276 g PEI-800, and 1.035 g ZnS.

Compounded formulations were placed in a 37° C. incubating oven, astainless steel thermocouple was inserted into each sample containerthrough the cap, and samples were monitored closely for temperaturevariation and time. FIG. 25 illustrates the exothermic behavior of eachpolymer while setting. Samples become set just before the maximumexothermic levels are recorded.

In other reactions, first components 5.7.1, 5.7.2, and 5.7.3 werecompounded with a stoichiometric amount of PEI-800 and from 0-15% ofZnS. Compounded formulations were placed in a 37° C. incubating oven andexothermic data was measured as described above. Maximum exothermictemperature are shown in Table 17.

TABLE 17 Catalyst ° C. Time (min) 5.7.1. + PEI-800 None 62 38  3% ZnS 6630 10% ZnS 66 31 15% ZnS C090 51 43 5.7.2. + PEI-800 None 120 25  3% ZnS56 30 10% ZnS 53 33 15% ZnS C091 64 27.5 5.7.3. + PEI-800 None 125 19 3% ZnS 128.5 18.5 10% ZnS 83 23 15% ZnS C092 58 24

Data in Table 15 for 5.7.1, and 5.7.3 indicates that increasing thelevel of catalyst generally lowers maximum exothermic temperature andincreases setting time. Sample 5.7.2, however, demonstrated the oppositeeffect when moving from 10% to 15% catalyst, since the reactiontemperature increased and reaction time decreased.

In other experiments, 5% ZnO (w/w) was added to 5.7.1, 5.7.2, and 5.7.3epoxide systems with 5%, 10% or 15% ZnS. The rise in temperature overtime shown in FIG. 26 indicates that ZnO further decreases the exothermrelative to systems with 15% ZnS shown in FIG. 25.

The preceding example indicates that certain epoxy cement systemsaccording to the invention have desirable exothermic properties. Suchepoxy systems are expected to provide excellent hydrophobiccharacteristics. The preceding example also indicates the value of usingother aromatic epoxy compounds, such as Bisphenol A propoxylate (1PO/phenol) diglycidyl ether, in the first component of the invention.The preceding example (in combination with other Examples disclosedherein) indicates that the second component for these epoxy systems canbenefit from the use of polyethyleneimine doped with amino acids, suchas cysteine, polycysteine, tyrosine or polytyrosine.

Moreover, epoxy cement systems of the invention can be further set withcuratives other than amine, such as polysulfides, polyamides,polyimides, polyamic acid, polyols, polyanhydrides and polyaldehydes.The neat epoxy cement further filled with calcium phosphates, such asnano powder of hydroxyapatite, tricalcium phosphate, calcium carbonate,calcium sulfate and bioglass at a loading from 0% to 99% (w/w), for eachindividual powder or in any combinations.

Example 23

The following example illustrates the dough time characteristics ofcertain cement products of the invention.

First product: Trans-cyclohexanediamine: (t-CHDA) (0.571 gm) was mixedwith Epomin™ SP003 (PEI with approximate molecular weight of about 300,available from Shinwoo Advanced Materials, Seoul, Korea) (0.354 gm) andcompounded with PETA (1.610 gm). Dough time was 1 minute and maximumtemperature was 45° C. at 1 minute. Reverse osmosis (RO) purified waterwas added after 3 minutes. The water turned clear to amber clear. WaterpH on first day was about 10, on second day about 9, and after threeweeks pH was about 6. The polymer was clear and stuck to the side ofvial.

Second product: t-CHDA (0.612 gm) and tetramethylamminium hydroxide(0.034 gm) were mixed with PETA (1.120 gm). Dough time was over 8minutes and maximum temperature was 42° C. Water was added after 9minutes. Water was clear to amber clear. Water pH on first day was about10, on second day about 7, and after three weeks pH was about 6. Polymerwas white.

In the following experiments C067 represents a mixture of CHDA andm-phenylene diamine (m-PDA) with one to one mole ratio.

Third product: C067 (0.578 gm) was mixed with PETA (1.034 gm). No doughformed after 35 minutes and maximum temperature was 28° C. Water addedafter 9 minutes produced a light greenish-blue solution. Water pH onfirst day was about 7, on second day about 7, and after three weeks pHwas about 6. Polymer was clear.

Fourth product: C067 (0.591 gm) and DABCO (0.100 gm) were mixed withPETA (1.032 gm). No dough formed after 23 minutes and maximumtemperature was 35° C. Water added after 24 minutes produced a lightgreenish-blue solution. Water pH on first day was about 8, on second dayabout 7, and after three weeks pH was about 5.5. Polymer was white.

Fifth product: C067 (0.599 gm) and EPOMIN™ SP-003 (0.286 gm) were mixedwith PETA (1.768 gm). Dough time was 2 minutes and maximum temperaturewas 35° C. Water added after 3 minutes turned a light teak clearsolution. Water pH on first day was about 9, on second day about 9, andafter three weeks pH was about 6. Polymer was clear.

Sixth product: C067 (0.598 gm) and EPOMIN™ SP-003 (0.050 gm) were addedto PETA (1.011 gm). Dough was 9 minutes and maximum temperature was 31°C. after 2 minutes. Water added after 10 minutes turned lightgreenish-blue clear water solution. Water pH on first day was about 8,on second day about 7, and after three weeks pH was about 5.5. Polymerwas clear.

Seventh product: C067 (0.597 gm) and EPOMIN™ SP-003 (0.092 gm) wereadded to PETA (1.654 gm). Dough was 9 minutes and maximum temperaturewas 28° C. in 2 min. Water added after 10 minutes turned lightgreenish-blue solution. Water pH on first day was about 9, on second dayabout 7, and after three weeks pH was about 5. Polymer was clear.

The preceding example shows that Epomin™ SP-003 can shorten dough timeto under 10 minutes. Epomin™ SP-003 is a PEI with approximate molecularweight of about 300 Da and a primary to secondary to tertiary amineratio of 45:35:20.

Example 24

The following example illustrates the dough time characteristics ofcertain cement products of the invention.

Mixtures 9A (PEI-800 (21.601 gm, liquid) and guanidine carbonate (7.304gm, crystals)), 9B (PEI-800 (21.605 gm, liquid) and arginine (8.744 gm,crystals)), and 9C (PEI-800 (21.590 gm) (liquid) and cysteine (4.807 gm)(crystals)) were each made by stirring the indicated components andheating in a laboratory oven at 60° C. over two days. The mixturesremoved from the oven were phase separated into two layers, with a cakesettlement on the bottom. Mixtures were stirred for several minutes to aputty-like finish, and then they were placed on a hotplate with atemperature of about 50° C. (except for mixture 9A, which containsguanidine).

Mixture 9D was made by mixing E(2)BisDA:BisGA with 1:1 mole ratio.

Eighth cement product: 9D (4.973 gm) was mixed with 9A (1.072 gm) in a 5ml vial. It formed viscose glue-like solution quickly. Filling straw wastaken after 2 minutes. No exotherm observed. Mixture had a dough time of3 minutes. After 4 minutes RO water was added to the vial. Both the vialand the straw were placed in a 37° C. oven. After 45 minutes, thepolymer hardened like a rock and appeared to be completely dry.

Ninth cement product: 9D (5.343 gm) and 9B (1.012 gm) were mixed in a 5ml vial. Maximum temperature was 34° C. in 2 minutes. After 3 minutes ofmixing a filled straw was taken. After 4 minutes RO water was added tothe vial. Both the vial and the straw were placed in a 37° C. oven.After 17 minutes, the compound was still sticky. After 25 minutes thecompound was solidified and tacky. After 37 minutes the compound wasstill tacky.

Tenth cement product: 9D (3.270 gm) and 9C (0.686 gm) were mixed in a 5ml vial. No exotherm observed. Filled a straw was taken after 1 minutes.Mixture had a dough time of 3 minutes. After 5 minutes RO water wasadded to the vial. Both the vial and the straw were placed in a 37° C.oven. After 7 minutes, the mixture hardened and turned tacky. After 18minutes, was dried and tack-free.

After 70 minutes, the eighth, ninth and tenth cement product werehardened like a rock and dry to touch. Vials filled with water had noobservable dissolution debris floating or precipitating.

Eleventh cement product: 9D (5.148 gm) and 9A (1.229 gm) were mixed in a5 ml vial. No exotherm was observed. Filled a straw after 1.5 minutes.The mixture had a dough time of 3.5 minutes. After 5 minutes RO waterwas added to the vial. Both the vial and the straw were placed in a 37°C. oven. Both the straw and vial were placed in the 37° C. oven. After15 minutes, the mixture was hardened and felt tacky.

Example 25

The following example illustrates fast resorbable cement products of theinvention. The o-diaminocyclohexane used was DYTEK™ DCH-99 from Invista(Wilmington, Del.).

First resorbable product: PETA and o-diaminocyclohexane (2:1 w/w) weremixed. Dough time was 20 minutes and exotherm temperature rise was 35°C. within 2 minutes. This product did not set as fast as aPETA:o-diaminocyclohexane at 1:1 [(meq c=c):(meq primary amine)], whichhad a temperature rise to 58° C. in 2 minutes and dough time of 10minutes.

Second resorbable product: PETA (1.987 gm) was mixed witho-diaminocyclohexane (0.581 gm). No dough was formed after 2.5 hours.Temperature rise was 38° C. within 3-4 minutes. After 3-4 minutes astraw was filed and plugged and put it in 37° C. incubator oven.

Third resorbable product: PETA (2.027 gm was mixed witho-diaminocyclohexane (1.171 gm). Dough time was 10 minutes andtemperature rise was 58° C. in 2 minutes. A straw was filled after 3-4minutes and placed in incubator oven after 5 minutes. The vial wasfilled with RO water after 7 minutes. After 28 minutes the mixture was atacky, soft, flexible, and clear solid. Mixture became a harder solidafter 1.5 hours.

Fourth resorbable product: PETA (2.003 gm), o-diaminocyclohexane (0.670gm), and PEI-800 (0.434 gm) were mixed. Dough was 1.5 minutes andtemperature rise was 38° C. in 1 minute. Mixture solidified into arubbery solid within 3 minutes.

Fifth resorbable product: PETA (19.985 gm) and o-diaminocyclohexane(11.436 gm) were mixed. The mixture was initially very fluid. Afterstirring, temperature rose from 17° C. to 95° C. within 2 minutes. Thewhole mixture set-up after 4 minutes of mixing.

All leftover vials of the first through fifth resorbable products weresoaked with RO water. The solution was crystal clear. The products werefully dissolved after 3 days.

Example 26

The following example illustrates hydrolytically stable cement productsof the invention that include an aromatic diamine. In the followingexample, 9D refers to mixture 9D of Example 24.

First aromatic diamine product: EPOMIN™ SP003 (1.030 gm) and 9D (4.979gm) initially formed a thick mixture. After stirring, temperature wentup from 17° C. to 45° C. within 2 minutes. The mixture set-up within 4minutes of mixing.

For the following products, solution 16 A was made by mixing DYtek™DCH99 (57.136 gm, liquid) with m-PDA (58.185 gm, flakes), heating themixture at 50° C. for 4 hours until all the m-PDA dissolved to a clearbrownish low viscosity liquid.

Second aromatic diamine product: 9D (4.726 gm) was mixed with 16A (0.586gm). Temperature rose from 22° C. to 34° C. within 2 minutes. A strawwas filled after 3 minutes of mixing. After 26 minutes, no dough wasobserved and the mixture was very sticky. After 100 minutes the mixtureremained a sticky soft gel. Water added to the vial resulted in a smallquantity of oily droplets floating on the top of water.

Third aromatic diamine product: 9D (5.385 gm), 16A (0.628 gm), andPEI-800 (0.416 gm) were mixed. Temperature rose from 22° C. to 41° C. in2 minutes. A straw filled after 2 minutes. After 30 minutes the mixtureis solid and tacky. After 50 minutes later the mixture is dry to thetouch.

Fourth aromatic diamine product: 9D (5.079 gm), 16A (0.493 gm) andPEI-800 (0.240 gm) were mixed. Temperature rose from 22° C. to 37° C. in2 minutes. A straw was filled after 4 minutes. After 30 minutes themixture was very sticky and not gel. After 1 hour, the mixture was asticky soft gel. The product did not include enough PEI.

Fifth aromatic diamine product: 9D (4.346 gm), DCH99 (0.509 gm) andPEI-800 (0.121 gm) were mixed. Temperature rose from 22° C. to 36° C. in2 minutes, After 3 minutes a straw was filled. After 7 minutes, R.O.water was added to the vial. After 30 minutes, mixture was still softand sticky. After 50 minutes, gelled and tacky. After 16 hours thepolymer hardened and dried. No dissolution into water was observed after16 hours.

In the following products, 20A was formed by premixing mPDA (10.862 gm)and diethylenetriamine (DETA) (10.323 gm) at 1:1 mole ratio. Afterheating for 2 hours at 50° C., the mixture is amber clear solution. DETAis available from Aldrich as diethylenetriamine reagent plus, 99%,CAS#111-40-0.

Sixth aromatic diamine product: 9D (4.554 gm) 30A (0.448 gm), DytekDCH99 (0.303 gm), and PEI-800 (0.171 gm) were mixed. Temperature rose to38° C. from 22° C. with in 2 minutes. After 4 minutes straw was filled.After 6 minutes, add R.O. water into the vial with leftover compound.After 15 min, dough yet very sticky, after 30 minutes it was hard andtacky, after 1 hours, the mixture had a thermoplastic elastomer likefinish and dried to touch. After 20 hours the polymer had hardened likea rock. After 20 hours, no dissolution into water observed in the vial.

Seventh aromatic diamine product: 9D (2.875 gm), 20A (0.396 gm) andPEI-800 (0.352 gm). Temperature rose up to 41° C. from 22° C. in 2minutes. After 3.5 minutes mixture was viscous, the filled straw pullingfibers. After 10 minutes, the mixture was harder and slightly sticky.After 13 minutes the hardened mixture was somewhat tacky. After 20minutes the hardened compound was not tacky.

Eight aromatic diamine product: 20A (0.699 gm) and 9D (4.602 gm) weremixed. Temperature rose to 35° C. Straw was filled after 8 minutes. Thecompound hardened after 35 minutes but was still sticky. After 1 hourthe solution was hardened and not tacky.

In the following products composition 23A is a white suspension ratherthan a clear solution of Melamine (white powder) in DETA (watery liquid)at 1:1 mole ratio. C066 is a 1:1 weight ratio of E(2)BisDA and BisGA.Melamine is C3H6N6. (6 members heterocyclic ring structure with 3pendent primary amine groups, available from Aldrich (CAS #108-78-1).

Ninth aromatic diamine product: 9D (4.902 gm) and 23A (0.569 gm) weremixed. Temperature rose to 33° C. Straw was filled after 7 minutes.After 30 minutes, the compound was still soft and sticky.

Tenth aromatic diamine product: DETA (0.271 gm) and E (1.5)BisDA (1.837gm) were mixed. Temperature rose to 36° C. from 22° C. in 2 minutes.After 2 hours in 37° C. the compound was solid and not sticky.

Eleventh aromatic diamine product: DETA (0.337 gm) and E (1.5) BisDA:(1.856 gm) were mixed. Temperature rose to 47° C. from 22° C. in 2 min.After 1.5 hours in 37° C. oven, the mixture was solidified and somewhatsticky.

Twelfth aromatic diamine product: 20A (0.436 gm) and E (1.5)BisDA (1.820gm) were mixed. Temperature rose to 36° C. within 2 minutes. After 1.5hours in 37° C. oven the mixture was solidified and non-sticky.

Thirteenth aromatic diamine product: 20A (0.357 gm) andglycidylmethacrylate (0.728 gm) were mixed. No reaction was observedafter 10 minutes at room temperature with vigorous stirring, Heated on ahotplate (43° C.) for 1 hour. Filled a section of straw while hot. After1.5 hours the mixture very sticky and highly viscous and glue-like.After 4 hours, the mixture solidified and was still tacky.

Fourteenth aromatic diamine product: 20A (0.917 gm), PEI-800 (0.919 gm)and E (1.5)BisDA (7.200 gm) were mixed. Temperature rose to 44° C. from22° C. in 2 minutes. Dough time was 5 minutes. After 5 minutes mixturewas dry to touch. The mixture was rubbery hard in 15 minutes. After anhour the mixture had the hardness of a thermoplastic elastomer.

Fifteenth aromatic diamine product: 20A (2.157 gm), PEI-800 (0.473 gm),and E (1.5)BisDA (10.867 gm) were mixed. Temperature rose to 50° C. from22° C. in 3 minutes. Filled straw after 7 minutes was very sticky. After0.5 hours the mixture solidified as rubbery sticky solid. After 1 hourthe mixture was a clear, shiny, somewhat rubbery solid.

The preceding example provides examples of hydrolytically stable cementproducts of the invention that include an aromatic diamine.

Example 27

The following example provides cement products of the invention thatinclude high glass transition temperature enones. Generally, theproducts include a triacrylate crosslinker and a resin (Part A) and acurative (Part B).

In one product: Part A includes E(2)BisDA (31.7123 gm or 0.1496 meq),BisGA (18.2877 gm or 0.0756 meq), tris(2-hydroxyethyl) isocyanuratetriacrylate (SR368) from Sartomer (5.2101 gm or 0.03544 meq).4.7282×10-3 meq/gm. Part B includes linear polyethyleneimine (PEI-1)(Aldrich Cat#468533). Both Parts are loaded with 33.34% HA SD050 powder.The product increases hydrophobicity of polymer and improvescompression/dissolution properties of injectable bone cements.

Other Products improve hydrophobicity of polymer are made by combiningthe following Part A diacrylate or triacrylate with the following Part Bcurative.

Part A Dicacrylates:

-   -   1. E(2)BisDA: Ethoxylated (2) bisphenol A diacrylate (Scientific        Polymer Products (SPP)), inhibited with 100 ppm MEHQ, meq=212    -   2. BisGA: Bisphenol A glycerolate (1 glycerol/phenol)        diacrylate, inhibited with 4,500 ppm MEHQ, meq=242    -   3. DEGDA: Sartomer SR230 diethyleneglycol diacrylate, inhibited        with 115 ppm MEHQ, 92.36%, meq=107    -   4. DPGDA: Sartomer SR508 dipropyleneglycol diacrylate (inhibited        with 185 ppm MEHQ), 84%, meq=121    -   5. IBGDA: Sartomer SR212 1,3-butyleneglycol diacrylate,        inhibited with 517 ppm HQ, 80.9%, meq=99    -   6. 1,4-butanediol diacrylate, tech, 90% (Aldrich), meq=110    -   7. 1,6-hexanediol diacrylate, tech, 80%, inhibited with 100 ppm        MEHQ, meq=141.4    -   8. trimethylolpropane benzoate diacrylate (Aldrich),    -   inhibited with 1000 ppm MEHQ, meq=173

Part A Triacrylates: (Crosslinkers)

-   -   9. GPTA: Glyceryl propoxy triacrylate (Scientific Polymer        Products (SPP)), inhibited by 300 ppm MEHQ, meq=142.67    -   10. PETA: Pentaerythritol triacrylate (SPP), inhibited by 350        ppm MEHQ) meq=99.43    -   11. THEICUTA: Sartomer SR-368 Tris(2-hydroxy ethyl)isocyanurate        triacrylate, inhibited by 85 ppm MEHQ, solid, 99.96%, meq=141    -   12. TMPTA: Trimethylolpropane triacrylate (Sigma-Aldrich),        inhibited by 100 ppm MEHQ, meq=109

Part B Curatives:

-   -   13. Polyethyleneimine (PEI-2, Average Molecular Weight 800,        branched) meq=43    -   14. Ethyleneimine, Oligomer Mixture, (PEI-1, Average Molecular        Weight 423), with 5-20% 112-57-2 TEPA, meq=43    -   15. t-DACH: Trans-1,2-diaminocyclohexane, meq=28.5    -   16. Dytek A: 2-methyl 1,5-pentanediamine, 99% (Sigma-Aldrich),        meq=29    -   17. Spermidine, 99% (Alfa Aesar, Ward Hill, Mass.), meq=29    -   18. 1,4-diaminobutane, 99% (Aldrich), meq=22    -   19. Spermine, 97%, (Sigma), meq=33.7

More specifically, a first series of products is made by mixing 1:1 meqratio of Part A (each of 1-12) and Part B (each of 13-19), respectively.A second series of products is made by mixing 1:1.2 meq ratio of Part A(each of 1-12) and Part B (each of 13-19), respectively. A third seriesof products is made by mixing 1:0.8 meq ratio of Part A (each of 1-12)and Part B (each of 13-19), respectively.

The preceding example provides cement products of the invention thatinclude high glass transition temperature enones or higher alkylaliphatic diamines.

Example 28

The following example provides cement products of the invention suitablefor hybrid reactions that includes Michael additions and free radicalpolymerization.

In the following products: Part 26A is a premix of BisGMA and E(2)BisDA(1:2 mole ratio) (e.g., made with BisGMA (52.512 gm) and E(2)BisDMA(90.544 gm). Part 26B is a premix of E(2)BisDA and BisGA made by mixingBisGA (48.642 gm) and E(2)BisDA (85.224 gm).

For the first series of hybrid products: Part A1 is made by mixing 1:1(w/w) of 26A and 26B to make (combined acrylates and methacrylates) with0.004365 meq/gm (229 dalton/mole equivalent). The mixture is doped with0.05% (w/w) of N—N-dimethyl-p-toluidine to make Part A1. Part B1includes PEI-1 doped with 10%, 5%, or 2.5% (w/w) benzoyl peroxide (BPO,75% (w/w) in water from Alfa Aesar, Ward Hill, Mass.). Part A1 is mixedwith each of the three BPO-doped versions of Part B1 at a ratio of 6:1(w/w) or 12:1 (w/w) to make six hybrid products.

For the second series of hybrid products: Part A2 is made by mixing 70.0gm of 26A with 14.267 gm glyceryl propoxy triacrylate (GPTA) on a hotplate set to about 50° C.) so as to de-gas until a clear warm and lowviscose fluid is obtained. The resulting product has 0.004806 meq/gm(208 dalton/mole equivalent). This product is further mixed with 26B in1:1 (w/w) ratio to form Part A2, which has meq of 215 dalton. Part A2 isdoped with 0.05% DMPT and mixed with the same Part B1 set forth above inthe following ratios: PartA2:PartB1=5:1 (w/w) and Part A2:Part B1=10:1(w/w)

Example 29

The following example provides a cement product of the invention.

Poly[(phenyl glycidyl ether)-co-formaldehyde](PPGEF) (CAS #28064-14-4)14.218 gm was dissolved in 16.727 gm of ethoxylated (2) bisphenol Adiacrylate (E(2)BisDA) (CAS#64401-02-1), heated to 60° C. and stirred toa homogeneous solution. The solution was cooled to room temperatures toyield 28.600 gm of hybrid Resin A.

In a 60 ml NALGENE™ PP flat bottom bottle, 4.704 gm of PEI-800 was addedto Resin A with vigorous stirring for 30 seconds. Stirred product waspoured into SS molds. Within 5.5 minutes (work time) specimens formedwith a diameter of one quarter inch and length of one half inch. SSmolds were sealed at both ends with a piece of SS block each. Molds werethen clamped and placed in a 37° C. incubator oven for curing. The SSmolds were opened after 2 hours and specimens were punched out from themolds. They were divided into 2 trays. One filled with 1×SBF andcovered. While the other trays were exposed to air. Both trays wereplaced in a 37° C. oven before subject to compression testing.Compression testing results are shown in FIG. 26. Each data point is anaverage of tests on 5 specimens. Compression mechanical strength is inthe range of 85 MPa for dried control specimen and 75 MPa for 1×SBF bodytemperature soaked specimen. Both are above a specification for weightbearing bone cement. In a experiment, an exothermic temperature rise wasdetermined to be around 45° C. within 7-10 minutes. The cement productset hard after 1 hour.

The foregoing example demonstrates a cement product of the inventionwith good hardness and excellent dimension stability in 1×SBF.

Example 30

The following example provides a cement product of the invention with afirst component that includes an isocyanate and a second component thatincludes a hindered amine.

In a 20 ml vial, 1.234 gm of bisphenylisocyanate methylene (MG-0725A)from Dow Corning (Midland, Mich.) was reacted with 2.725 gm of asparticester (Desmophen NH 1420) from Bayer (Pittsburgh, Pa.). The reaction wasstirred to a homogenous mixture within 1 minute. Temperature rose from25° C. to 37° C. in 1 minute. Temperature reached a maximum at 45° C.after four minutes. The working time was 2 minutes and the reactionbecome a hard dough in 4 minutes and 15 seconds. The cement product wascompletely set (rock hard solid) in 10 minutes.

Example 31

The following example provides a cement product of the invention.

In a 20 ml vial, 1.1046 gm of trimethylolpropane triacrylate (TMPTA)(Sigma-Aldrich) was reacted with 0.6766 gm of Dytek A (Sigma-Aldrich).The reaction was stirred to a homogenous mixture within 1 minute. Thetemperature rose from 25° C. to 53° C. in 2 minute. The working time was10 minutes and the neat cement set to dried to touch in 20 minutes.

Example 32

The following example provides a cement product of the invention thatcomprises a second component with a naturally occurring amine.

In a 20 ml vial, 1.3294 gm of 1,4-butanedioldiacrylate from Aldrich, wasadded with 0.6638 gm trimethyloipropane triacrylate (TMPTA) fromSigma-Aldrich. The mixture was stirred for 30 second, it was thenreacted with 0.526 gm of spermidine from Alpha Aesar (Ward Hill, Mass.),and the reaction was stirred to homogenous mixture within 1 minute. Thetemperature rose from 25° C. to 57° C. in 2 minute. The working time was3 minutes and the neat cement set to dried to touch in 5 minutes.

Example 33

The following example provides another cement product of the inventionthat comprises a second component with a naturally occurring amine.

In a 20 ml vial, 1.3924 gm 1,4-butanediol diacrylate from Aldrich wasreacted with 0.4274 gm of spermidine from Alpha Aesar. The mixture wasstirred to homogenous mixture within 1 minute. The temperature rose from25° C. to 48° C. in 2 minutes. The working time was 10 minutes and theneat cement set dried to touch in 30 minutes.

The foregoing example demonstrates the desirable exotherm, set time, andhardness properties of a cement product that includes an isocyanate anda hindered amine.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

The invention claimed is:
 1. A method of forming a cement product, themethod comprising: (i) mixing a first component and a second component,wherein: the first component comprises a polymerizable resin thatcomprises two or more acrylate groups; and the second componentcomprises a compound selected from the group consisting of putrescine(1,4-diaminobutane), spermidine, and spermine, and wherein the firstcomponent, the second component, or both the first and second componentscomprise a bioceramic filler; (ii) allowing the first component andsecond component to react with each other in a polymerization reactionat room temperature to produce an orthopedic or dental cement having acompressive strength of about 20 MPa to about 250 MPa, and (iii)allowing the polymerization reaction mixture to set at about 37° C.,wherein the polymerization reaction mixture does not exceed a maximumtemperature of 60° C. for a period of one minute.
 2. The method of claim1, wherein the polymerization reaction mixture does not exceed a maximumtemperature of 50° C. for a period of one minute.
 3. The method of claim1, wherein a dry-to-touch finish of the orthopedic or dental cement isachieved in about 30 minutes or less.
 4. The method of claim 1, whereina dry-to-touch finish of the orthopedic or dental cement is achieved inabout 15 minutes or less.
 5. The method of claim 1, wherein adry-to-touch finish of the orthopedic or dental cement is achieved inabout 10 minutes or less.
 6. The method of claim 1, wherein the secondcomponent is blended or grafted with (a) one or more amino acidsselected from the group consisting of L-phenylalanine, L-tryptophan,L-arginine, L-cysteine, L-cysteine, L-tyrosine, L-lysine, L-histidine,(b) one or more derivatives of selected from the group ofL-phenylalanine, L-tryptophan, L-arginine, L-cysteine, L-cysteine,L-tyrosine, L-lysine, and L-histidine derivatives, or (c) a combinationof two or more of the amino acids or derivatives thereof of (a) and (b).7. The method of claim 1, wherein the first component comprises acompound selected from the group consisting of bisphenol A glycerolatedi(meth)acrylate, non-alkoxylated trimethylpropane tri(meth)acrylate(TMPT(M)A), ethoxylated(15) TMPT(M)A, ethoxylated (9) TMPT(M)A,ethoxylated (6) TMPTA, ethoxylated (3) TMPTA, propoxylated (3) TMPT(M)A,propoxylated (6) TMPT(M)A, propoxylated (5) glycerol ethoxylatedbisphenol-A-triacrylate, ethoxylated (2) bisphenol A diacrylate(E(2)BisDA), ethoxylated(4) bisphenol A diacrylate (E(4)BisDA),trimethylolpropane benzoate diacrylate, pentaerythritol triacrylate,pentaerythritoltetraacrylate, butanedioldiacrylate, hexanedioldiacrylateand mixtures thereof.
 8. The method of claim 1, wherein the firstcomponent comprises trimethylolpropane triacrylate.
 9. The method ofclaim 1, wherein the first component comprises non-alkoxylatedpentaerythritol triacrylate.
 10. The method of claim 1, wherein thefirst component comprises E(2)BisDA, E(4)BisDA, trimethylolpropanebenzoate diacrylate, 1,4-butandioldiacrylate, 1,3-butanedioldiacrylate,1,6-hexanediol diacrylate, or a mixture thereof.
 11. The method of claim1, wherein the second component further comprises one or more syntheticpolyamine selected from the group consisting of2-methyl-1,5-pentamethylenediamine, 2-ethyl-1,3-trimethylenediamine,N-(3-Aminopropyl)-1,3-propanediamine, diethylenetriamine (DETA),triethylenetetramine (TETA), and polyethyleneimine (PEI).
 12. The methodof claim 11, wherein the first component comprises trimethylolpropanetriacrylate; and the second component further comprises2-methyl-1,5-pentamethylenediamine.
 13. The method of claim 12, whereinthe first component comprises bisphenol A diglycidyl ether 33-67% w/w,trimethylolpropane triacrylate 33-67% w/w, and, optionally,trimethylolpropane benzoate diacrylate 0-33% w/w; and the secondcomponent comprises a mixture of spermidine in an amount of at least 33%w/w and 2-methyl-1,5-pentamethylenediamine in an amount up to 67% w/w.14. The method of claim 1, wherein the first component comprisestrimethylolpropane triacrylate; and the second component furthercomprises a polyamine selected from the group consisting of 2methyl-1,5-pentamethylenediamine, 2-ethyl-1,3-trimethylenediamine, or acombination thereof.
 15. The method of claim 4, wherein the firstcomponent comprises sorbitol polyglycidyl ether 0-40% w/w,trimethylolpropane triacrylate in an amount up to 30% w/w, and1,4-butanediol 0-20% w/w such that the weight percent of sorbitolpolyglycidyl ether, the weight percent of trimethylolpropanetriacrylate, and the weight percent of 1,4-butanediol total 100% w/w;and the second component comprises spermidine 20-100% w/w and a secondpolyamine compound selected from the group consisting of2-methyl-1,5-pentamethylenediamine and 2-ethyl-1,3-trimethylenediamine,in an amount up to 80% w/w.
 16. The method of claim 1, wherein thebioceramic filler comprises tricalcium phosphate (α-TCP, β-TCP),hydroxyapatite, calcium phosphate, or a mixture thereof.
 17. The methodof claim 1, wherein the first component and/or the second componentfurther comprises an initiator or catalyst.
 18. The method of claim 17,wherein the initiator is a photoinitiator selected from the groupconsisting of a quinone photoinitiator,2-benzyl-2-(dimethylamino)-4′-morpholino-butyrophenone, or mixtures of2-hydroxyethy-2-methyl-1-phenyl-1-propanone, anddiphenyl(2,4,6-trimethylbenzyl)phosphine oxide.
 19. The method of claim17, wherein the first component and/or the second component comprises acatalyst and the catalyst comprises a benzoyl peroxide (BPO) catalyst oran amine-containing catalyst.
 20. The method of claim 1, wherein thefirst component and the second component are each packaged in (i) aseparate chamber of the same container or (ii) a separate container. 21.The method of claim 20, wherein (i) the same container is adapted forinjecting cement formed from the first and second component or (ii) eachseparate container is adapted for injecting cement formed from the firstand second component.